Plasma-Targeted Proteomic and Lipidomic Profiling of MASLD, MASH, and Hepatitis C Virus Infection

Plasma-Targeted Proteomic and Lipidomic Profiling of MASLD, MASH, and Hepatitis C Virus Infection | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Plasma-Targeted Proteomic and Lipidomic Profiling of MASLD, MASH, and Hepatitis C Virus Infection Suzumi M Tokuoka, Fumie Hamano, Ayako Kobayashi, Masaya Sugiyama, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7675910/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Feb, 2026 Read the published version in Clinical Proteomics → Version 1 posted 10 You are reading this latest preprint version Abstract Background Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are chronic liver diseases characterized by lipid accumulation and persistent inflammation, often progressing to fibrosis or hepatocellular carcinoma (HCC). Hepatitis C virus (HCV) infection shares overlapping pathological features, including chronic inflammation and fibrogenesis. Despite their prevalence, reproducible molecular markers to distinguish disease stages or inform treatment monitoring remain limited. Methods We conducted targeted proteomic and lipidomic profiling of several hundred plasma samples from Japanese patients diagnosed with MASLD, MASH, or HCV infection. Targeted proteomics quantified 184 plasma proteins using the Olink Proximity Extension Assay, and targeted lipidomics quantified approximately 500 phospholipid and triglyceride species using LC-MS-based selected reaction monitoring. Reproducibility was assessed across three independent cohorts. Results Seven proteins consistently exhibited differential abundance: CASP-8, CCL20, and CTSD were elevated in MASH, while SCF, MMP-3, TRAIL, and TWEAK were downregulated. Similar alterations were observed in HCV, indicating shared immune dysregulation. Lipidomic analysis revealed decreased ether-linked phosphatidylethanolamine (PE), increased ester-linked PE, and elevated saturated sphingomyelin in MASH, reflecting oxidative stress and impaired lipid metabolism. Triglycerides containing linoleic acid (18:2) were consistently reduced in MASH and correlated with CTSD, implicating lysosomal pathways. Correlation analyses indicated coordinated relationships between protein and lipid alterations, suggesting immune–lipid cross-talk during disease progression. Conclusions This study provides the first large-scale dual-omics plasma analysis in Japanese cohorts with MASLD, MASH, and HCV. Rather than establishing definitive diagnostic biomarkers, our results should be interpreted as reproducible, hypothesis-generating reference data. These findings provide a framework and resource for future studies aiming at risk stratification, therapeutic monitoring, and mechanistic validation in chronic liver disease. proteomics lipidomics multi-omics MASH MASLD HCV plasma clinical samples Figures Figure 1 Figure 2 Figure 3 Figure 4 1. Introduction Two of the most common forms of liver diseases have relatively recently been reclassified: Non-alcoholic fatty liver disease (NAFLD) is now Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), and non-alcoholic steatohepatitis (NASH) is now referred to as Metabolic Dysfunction-Associated Steatohepatitis (MASH) 1 . They are characterized by the accumulation of fat and inflammation in the liver, which can often become liver fibrosis, cirrhosis, and even HCC 2 . Therefore, early diagnosis and appropriate therapeutic interventions are crucial. MASLD is closely associated with obesity, type 2 diabetes, dyslipidemia, and other lifestyle-related diseases. The global prevalence of such diseases is estimated at around 25% 3 . Recently, lifestyle-related diseases have garnered attention as important clinical and public health challenges. MASH is a progressive form of MASLD, and requires speedier diagnosis, more advanced treatment and management 4 . Unfortunately, however, non-invasive biomarkers that more precisely diagnose these diseases and better monitor disease progression and treatment efficacy remain scant 5 . This study aims to generate reproducible reference data on proteomic and lipidomic alterations in MASLD and MASH, providing hypothesis-generating insights into disease progression and treatment response, and offering a framework to support future biomarker discovery and therapeutic development. To understand the characteristics of MASLD and MASH, individuals infected with HCV and undergoing treatment were used as the comparison group. Hepatitis C Virus (HCV) infection is recognized as a major chronic liver disease. Both MASLD/MASH and HCV are characterized by chronic inflammation, fibrosis, and increased risk of hepatocarcinogenesis. Therefore, HCV represents an informative comparator for delineating the shared and distinct pathogenic pathways of liver inflammation, fibrosis, and metabolic dysregulation. In contrast, collecting a critical mass of plasma samples from healthy individuals proved impractical because healthy people generally have no particular needs to seek medical help. In addition, rigorously excluding subclinical liver abnormalities in such populations is also challenging. For these reasons, healthy controls were not ─ or more precisely, could not be ─ included in this study. Proteomics was selected as an appropriate approach to investigate inflammatory, immune, and fibrotic signaling pathway since only plasma samples were available. Lipidomics was employed to capture the lipid metabolic alterations that are characteristic of chronic liver diseases. Accordingly, proteomic analysis was performed first, followed by lipidomic analysis. We have previously worked on integrating multi-omics approaches, including proteomics, lipidomics, and metabolomics 6 , 7 . However, increased measurement duration and costs, as well as the overwhelming amount of data, has compelled us to employ targeted lipidomics and targeted proteomics in this research. For targeted proteomics, Olink Proteomics' Proximity Extension Assay (PEA) 8 was utilized. Using the Olink Target 96 Series 9 with panels enables quantitative analysis of more than 1,000 proteins in human plasma; however, considering measurement time and costs, we limited our measurements to 184 proteins across 2 panels. Since the progression of MASLD and MASH involves not only fat accumulation but also inflammation and damage to the liver 9 , we selected the inflammation panel from the Olink Target 96 Series. Furthermore, since MASLD individuals are commonly associated with metabolic syndrome and have an increased risk of cardiovascular disease, Cardiovascular II and III panels were also candidates. We chose the Cardiovascular III panel to explore new mechanistic insights regarding the relationship between liver disease and cardiovascular outcomes 10 all the more because the panel includes fewer well-defined biomarkers. For targeted lipidomics, we analyzed some 500 types of phospholipids and triglycerides (TGs) using the Selected Reaction Monitoring (SRM) method of Liquid Chromatography/Mass Spectrometry (LC/MS) 11 . The methods we employed provide excellent sensitivity for measuring specific proteins and lipid molecules, ensuring quantitativeness. Dual-omics analysis was chosen as the method of research in order to uncover new knowledge regarding disease mechanisms and related therapeutic targets all the more because of the robust synergy provided by the integration of two different types of omics data. This, in turn, enabled us to assess the relationships between liver diseases and proteins or lipids. To the best of our knowledge, this represents the first report of conducting both proteomic and lipidomic analyses at a scale of several hundred plasma samples from Japanese patients diagnosed with chronic liver diseases. 2. Experimental Section Demographic Characteristics Plasma samples from the biobank of the National Center for Global Health and Medicine (197 with MASLD, 81 with MASH and 188 with HCV) and from Saga University Hospital (39 with MASLD and 113 with MASH) were employed in this study. All 618 plasma samples used consisted of three cohorts (Table S1 ). A liver biopsy was performed to diagnose MASH. Due to the previously-mentioned potential difficulties in accurately diagnosing MASH and MASLD, a certain amount of concern that some of the disease specimens employed in this study might include cases with inaccurate diagnoses remained. Participation was voluntary, and all participants provided signed informed consent forms before registering to participate in this study. All samples from Cohort 1 were used for proteomics. Of Cohort 2 samples, 70 HCV, 77 MASLD, and 39 MASH plasma samples were used for proteomics; and 92 HCV, 81 MASLD, and 30 MASH samples were used for lipidomics. Of the Cohort 3 samples, 72 HCV, 114 MASLD, and 68 MASH plasma samples were used for proteomics; and 96 HCV, 94 MASLD, and 41 MASH were used for lipidomics. Given the limitations in sample volume and the finite availability of research reagents and other resources, performing both proteomics and lipidomics analyses on every sample within Cohort 2 and Cohort 3 was not consistently feasible. Nevertheless, the selection criteria for allocating samples to each analysis were established prior to obtaining the results, and subsequent measurements and analyses were conducted according to these predetermined criteria. Human Plasma Samples and Quality Control Sample This study received approval from the Research Ethics Committee of the Faculty of Medicine of the University of Tokyo (Approval numbers 2019282NI-(2), 2019283NI-(2), and 2019022NI). Ethical approval for this research was obtained from the Ethics Committee of The University of Tokyo Hospital in strict compliance with pertinent university, local, and national guidelines and regulatory standards. To control potential order-dependent systematic errors, the samples from different diagnostic groups were arranged in a dispersed pattern throughout the cohort's measurement sequence. To manage potential long-term drifts in LC-MS sensitivity, a stocked pooled sample consisting of randomly selected 1,000 serum samples was utilized as quality control (QC) samples in the measurement. Reagents Acetonitrile, 2-propanol (LC/MS grade), and ammonium formate (Wako special grade) from FUJIFILM Wako Pure Chemical Corp. (Osaka, Japan) were the reagents used. Ultrapure water was prepared using the Milli-Q system (Millipore, Billerica, MA, USA). All reagents for PEA proteomics were obtained from Olink Proteomics (Uppsala, Sweden). PEA Proteomics CARDIOVASCULAR III and INFLAMMATION panels obtained from Olink Proteomics (Uppsala, Sweden) were used. One µL plasma was used for each panel assay. This experiment utilized the robotic system Maholo equipped with an electronic multi-channel pipette. For the quantification process, the Fluidigm Biomark™ HS system or Olink® Signature Q100 system was used for real-time quantitative polymerase chain reaction (qPCR) analysis. Data was processed with the Olink NPX manager software and transformed to Olink’s NPX value, a relative protein quantification unit on a log2 scale. NPX values are derived from threshold cycle (Ct) values obtained through qPCR. Each panel was able to measure 92 proteins, and a total of 184 proteins were measured in two panels. This includes three proteins that were included as measurement targets in both panels. Data for 148 proteins detected from among 184 proteins across all 528 plasma samples in this study were used in the analysis. Lipidomics Measuring phospholipids and TGs was conducted by lipid extraction from plasma by adding 490µl of 2-propanol onto each 10 µL of plasma sample as described previously with minor modifications 7 . The plasma and 2-propanol were mixed with a vortex mixer for 15 seconds at room temperature, and stored at -30°C for one hour. The supernatant after centrifugation at 10,000 × g for 10 minutes was collected and transferred to a 384-well plate for measurements. For phospholipid measurements, LCMS-8060NX triple quadrupole mass spectrometers equipped with NexeraXS UHPLC (Shimadzu Co., Kyoto, Japan) were used. Shimadzu LabSolutions LCMS software version 5.112 (Shimadzu Co.) was used for instrument operation. Shim-pack Scepter Claris C18-120 columns (2.1 mm × 100 mm, 1.9 µm, Shimadzu Co.) were utilized for reversed-phase chromatography. The flow rate was 0.3 mL/min, and the column temperature was 50°C. Mobile phase A consisted of 20 mM NH4HCO2/water, and mobile phase B consisted of 20% acetonitrile and 80% 2-propanol (IPA). The pump gradient was programmed as follows: [time (%A/%B), B Curve setting as 0 unless stated]: from 0 min (70/30) to 0.5 min (70/30), to 14.5 min (10/90) with B Curve setting at -3, 14.6 min (3/97), 18.1 min (3/97), 18.2 min (70/30) and 21 min (70/30). The parameters for the mass spectrometer were set as follows: nitrogen gas used as a nebulizer was set at 2.5 L/min, and as a heating gas set at 10 L/min. The drying gas was set at 10 L/min. Argon gas was used for collision-induced dissociation. Interface temperature was 240°C. Heat block temperature was set at 400°C, and desolvation line temperature was set at 250°C. The injection volume was 3 µL. Table S2 shows SRM transitions for phospholipid measurement. The transition list was developed for phospholipid species that can be measured in human blood samples, based on preliminary experiments. These transitions utilize fragmentation for polar head groups in phospholipids or fragmentation for one of the two fatty acyl chains consisting of the lipids. Transitions that utilize fragmentation characteristics for vinyl ether linkage to fatty chains 12 were also used. To consistently represent the phospholipid species analyzed using these SRM, the following nomenclature was used: peaks were identified using SRM with fragmentation of polar head groups, the phospholipid name is represented by the lipid class, followed by the sum of the carbon atoms in the two fatty chains, and the sum of the double bonds in the two fatty chains (e.g., PC_38:6). For peaks identified using SRM with fragmentation of fatty acyl chains, the phospholipid name is represented by the lipid class and the number of carbon atoms and double bonds of the two fatty acyl chains. Following this, the number of carbon atoms and double bonds of the detected fatty acyl chain were specified (e.g., PC_18:2_20:4_FA_18:2 or PC_18:2_20:4_FA_20:4). In addition, for phospholipids containing one ether-linked chain, only the observed single fatty acyl chain is represented, because ether bonds do not typically produce fatty acyl fragments upon fragmentation. When several separated peaks were observed for the same SRM transition, they were named as peak 1, peak 2, and peak 3, in order of increasing retention time. For TG measurements, we used to the previously published LC/MS method with minor modifications11 LCMS-8040 triple quadrupole mass spectrometers equipped with Nexera UHPLC (Shimadzu Co.) were used. Shimadzu LabSolutions LCMS software version 5.112 (Shimadzu Co.) was used for instrument operation. Shim-pack Velox C18 (2.1 x 50 mm, 2.7 µm), was utilized for reversed-phase chromatography. The flow rate was 0.4 mL/min, and the column temperature was 45°C. Mobile phase A consisted of 20 mM NH4HCO2/water, and mobile phase B consisted of 100% acetonitrile, and mobile phase C consisted of 100% IPA. The pump gradient was programmed as follows: [time (%A/%B/%C)]: from 0 min (15/15/70) to 0.1 min (15/15/70), to 8.4 min (5/20/75), 9 min (5/20/75), 9.1 min (15/15/70), 11 min (15/15/70). The parameters for the mass spectrometer were set as follows: nitrogen gas used as a nebulizer was set at 2.5 L/min, and drying gas was set at 10 L/min. Argon gas was used for collision-induced dissociation. Heat block temperature was set at 400°C, and desolvation line temperature was set at 250°C. The injection volume was 4 µL. The list for SRM transitions for TGs is shown in Table S3. The transition list was developed for TG species that can be measured in human blood samples, based on preliminary experiments and the SRM transitions detected from all samples were used as result data. In the SRM transitions, Q1 was set as the parent ion of the ammonium adduct, and Q3 was set as the neutral loss of a fatty chain. The species-level TG name is expressed as the sum of carbon atoms and the sum of double bond equivalents of the three fatty chains. For the TG peaks observed in our SRM analysis, we named them by appending the number of carbon atoms and the number of double bonds of the fatty acyl chain detected as the neutral loss. Peak areas for each SRM were calculated by Traces software 13 . The QC measurements were performed every 12 samples, and raw peak areas were normalized using the systematic error removal by random forest (SERRF) method with the QC measurements 14 . Each normalized SRM peak value was summed for each lipid class, and the individual peak values were then expressed as a ratios to the summed lipid class values. Statistics One-way ANOVA and Student's t-test (where p-values were adjusted for false discovery rate (FDR) using the Benjamini-Hochberg procedure), and Pearson's correlation analysis were performed using MetaboAnalyst 6.0 software. 15 Box plots, volcano plots, and scatter plots were constructed using R software (version 4.4.2). 3. Results Targeted proteomics Targeted proteomics was conducted on plasma samples from 88 individuals (35 with MASLD and 53 with MASH) in Cohort 1, and eight proteins showed significant differences (FDR-adjusted p-values are less than 0.05) between MASLD and MASH (Table 1-1). To confirm reproducibility across different samples, targeted proteomics was conducted on plasma samples from 186 individuals (70 with MASLD, 77 with MASH, and 39 with HCV) in Cohort 2, revealing significant differences (FDR-adjusted p-values are less than 0.05) in 88 proteins (Table 1-2). Among these, 47 proteins marked with an asterisk ( * ) in Table 1-2 exhibited significant differences (FDR-adjusted p-values are less than 0.05) between MASLD and MASH, with seven proteins marked with ( # ) in Table 1-2 being reproduced in both Cohort 1 and Cohort 2. The seven proteins that were reproducible are as follows: CASP-8 (caspase-8), CCL20 (C-C motif chemokine ligand 20), CTSD (cathepsin D), MMP-3 (matrix metalloproteinase-3), SCF (stem cell factor), TRAIL (Tumor Necrosis Factor -related apoptosis-inducing ligand), and TWEAK (Tumor Necrosis Factor-related weak inducer of apoptosis). To confirm reproducibility using plasma samples collected from the same 186 individuals as Cohort 2 at different times, we conducted targeted proteomics on 254 plasma samples in Cohort 3 (some individuals had blood drawn twice on different days) (Table 1-3). The results indicated significant variations in 66 proteins (Table 1-3), with 28 proteins marked with an asterisk ( * ) in Table 1-3 showing significant differences (FDR-adjusted p-values are less than 0.05) between MASLD and MASH. Among these 28 proteins, seven proteins marked with ( # ) in Table 1-3 were reproduced across all three cohorts (Figures 1a-g). CASP-8, CCL20, and CTSD were elevated in MASH. MMP-3, SCF, TRAIL, and TWEAK were decreased in MASH. Comparing HCV and the other groups, the levels of CASP-8, MMP-3, TRAIL and TWEAK differed significantly from those in MASH in both Cohort 2 and Cohort 3 (Table 1-2 and Table 1-3). Correlation analysis of these seven proteins within all three cohorts revealed that the following pairs showed significant correlations with p < 0.01 across all three cohorts: CTSD/CCL20, MMP-3/SCF, MMP-3/TRAIL, MMP-3/TWEAK, SCF/TRAIL, SCF/TWEAK, and TWEAK/TRAIL. The correlation between CASP-8 and CCL20 was somewhat significant only in Cohort 1 at p = 0.016, whereas it was significant in Cohort 2 and Cohort 3 (p < 0.01) (Table S4, Figure S1). All correlations were positive. Table 1-1. Proteins with differential levels among clinical categories in MASH and MASLD in Cohort 1. Protein Uniprot ID FDR-adjusted p-value (BH) p-value SCF P21583 0.0276 0.00036 TWEAK O43508 0.0276 0.00037 CCL20 Q9NRJ3 0.0324 0.00088 t-PA P00750 0.0324 0.00094 MMP-3 P08254 0.0324 0.00120 TRAIL P50591 0.0324 0.00136 CASP-8 Q14790 0.0324 0.00153 CTSD P07339 0.0419 0.00227 FDR-adjusted p-values were adjusted under the Benjamini-Hochberg (BH) procedure. Table 1-2. Proteins with differential levels among clinical categories in Cohort 2. Protein Uniprot ID FDR-adjusted p-value (BH) Tukey's HSD CASP-8 *# Q14790 3.32E-16 3_MASH-1_HCV; 3_MASH-2_MASLD SELE * P16581 1.32E-11 3_MASH-1_HCV; 3_MASH-2_MASLD LDL receptor * P01130 2.29E-09 2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD IGFBP-2 P18065 5.20E-09 2_MASLD-1_HCV; 3_MASH-1_HCV FGF-21 Q9NSA1 4.74E-08 2_MASLD-1_HCV; 3_MASH-1_HCV MCP-3 * P80098 4.74E-08 3_MASH-1_HCV; 3_MASH-2_MASLD LAP TGF-beta-1 * P01137 3.19E-07 2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD SELP P16109 4.50E-07 2_MASLD-1_HCV; 3_MASH-1_HCV HGF * P14210 4.60E-07 3_MASH-1_HCV; 3_MASH-2_MASLD PAI P05121 4.60E-07 2_MASLD-1_HCV; 3_MASH-1_HCV FABP4 * P15090 1.42E-06 2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD CCL16 * O15467 4.36E-06 2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD ITGB2 * P05107 4.36E-06 3_MASH-1_HCV; 3_MASH-2_MASLD CASP-3 * P42574 5.90E-06 2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD IL-1RT2 * P27930 9.88E-06 2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD GP6 Q9HCN6 1.40E-05 2_MASLD-1_HCV; 3_MASH-1_HCV TNFSF14 O43557 1.40E-05 2_MASLD-1_HCV; 3_MASH-1_HCV IL-12B * P29460 1.70E-05 2_MASLD-1_HCV; 3_MASH-2_MASLD CXCL10 P02778 1.87E-05 2_MASLD-1_HCV; 3_MASH-1_HCV GDF-15 * Q99988 2.96E-05 2_MASLD-1_HCV; 3_MASH-2_MASLD IL7 * P13232 3.10E-05 2_MASLD-1_HCV; 3_MASH-2_MASLD CDCP1 * Q9H5V8 9.02E-05 2_MASLD-1_HCV; 3_MASH-2_MASLD OSM P13725 9.02E-05 2_MASLD-1_HCV; 3_MASH-1_HCV PDGF subunit A P04085 9.22E-05 2_MASLD-1_HCV t-PA *# P00750 1.04E-04 2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD CXCL9 Q07325 1.41E-04 2_MASLD-1_HCV; 3_MASH-1_HCV EN-RAGE P80511 1.55E-04 2_MASLD-1_HCV; 3_MASH-1_HCV PCSK9 * Q8NBP7 1.58E-04 3_MASH-1_HCV; 3_MASH-2_MASLD CCL20 *# P78556 1.63E-04 2_MASLD-1_HCV; 3_MASH-2_MASLD CHI3L1 P36222 0.00016305 2_MASLD-1_HCV RARRES2 * Q99969 1.63E-04 2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD TWEAK *# O43508 0.00019955 3_MASH-1_HCV; 3_MASH-2_MASLD IL10 P22301 0.00039744 2_MASLD-1_HCV; 3_MASH-1_HCV IGFBP-1 P08833 0.00042593 2_MASLD-1_HCV; 3_MASH-1_HCV IL-18BP O95998 0.00042593 2_MASLD-1_HCV STAMBP O95630 0.00051626 2_MASLD-1_HCV; 3_MASH-1_HCV JAM-A * Q9Y624 0.0005893 3_MASH-1_HCV; 3_MASH-2_MASLD CTSD *# P07339 0.00069465 2_MASLD-1_HCV; 3_MASH-2_MASLD TRANCE O14788 0.00090228 2_MASLD-1_HCV; 3_MASH-1_HCV TNFRSF9 * Q07011 0.0011404 2_MASLD-1_HCV; 3_MASH-2_MASLD CD163 * Q86VB7 0.0011675 2_MASLD-1_HCV; 3_MASH-2_MASLD SCF *# P21583 0.0011675 2_MASLD-1_HCV; 3_MASH-2_MASLD TIMP4 * Q99727 0.0011675 3_MASH-1_HCV; 3_MASH-2_MASLD CCL19 Q99731 0.0012062 2_MASLD-1_HCV; 3_MASH-1_HCV CXCL5 P42830 0.0012062 2_MASLD-1_HCV TRAIL *# P50591 0.0015401 3_MASH-1_HCV; 3_MASH-2_MASLD IGFBP-7 * Q16270 0.0015982 2_MASLD-1_HCV; 3_MASH-2_MASLD ADA * P00813 0.001641 3_MASH-1_HCV; 3_MASH-2_MASLD IL2-RA P01589 0.0017794 2_MASLD-1_HCV vWF * P04275 0.0020453 2_MASLD-1_HCV; 3_MASH-2_MASLD AP-N * P15144 0.002273 3_MASH-1_HCV; 3_MASH-2_MASLD TNFRSF14 * Q92956 0.0023743 3_MASH-1_HCV; 3_MASH-2_MASLD OPG _c O00300 0.0028465 2_MASLD-1_HCV; 3_MASH-1_HCV SLAMF1 Q13291 0.0028689 2_MASLD-1_HCV AZU1 P20160 0.0035057 2_MASLD-1_HCV; 3_MASH-1_HCV Gal-4 * P56470 0.0041724 3_MASH-2_MASLD MMP-9 P14780 0.0046299 2_MASLD-1_HCV IL-18R1 * Q13478 0.0052014 3_MASH-1_HCV; 3_MASH-2_MASLD OPG O00300 0.0057416 2_MASLD-1_HCV; 3_MASH-1_HCV TLT-2 Q5T2D2 0.0057416 3_MASH-1_HCV MMP-3 *# P08254 0.0073831 3_MASH-1_HCV; 3_MASH-2_MASLD TNFRSF10C O14798 0.0073831 3_MASH-1_HCV CD40 * P25942 0.0078302 3_MASH-1_HCV; 3_MASH-2_MASLD TGF-alpha P01135 0.0080214 2_MASLD-1_HCV CPA1 * P15085 0.008054 3_MASH-1_HCV; 3_MASH-2_MASLD CTSZ * Q9UBR2 0.010977 2_MASLD-1_HCV; 3_MASH-2_MASLD FAS * P25445 0.011105 3_MASH-2_MASLD CXCL11 O14625 0.011938 2_MASLD-1_HCV PON3 * Q15166 0.011938 3_MASH-1_HCV; 3_MASH-2_MASLD TNFB P01374 0.011938 2_MASLD-1_HCV ALCAM * Q13740 0.013208 3_MASH-2_MASLD CCL11 * P51671 0.013208 3_MASH-1_HCV; 3_MASH-2_MASLD LTBR * P36941 0.013626 3_MASH-2_MASLD MPO P05164 0.016457 2_MASLD-1_HCV; 3_MASH-1_HCV COL1A1 P02452 0.019287 3_MASH-1_HCV EGFR P00533 0.019287 2_MASLD-1_HCV CD244 * Q9BZW8 0.020751 2_MASLD-1_HCV; 3_MASH-2_MASLD IL-1RT1 P14778 0.025788 2_MASLD-1_HCV PD-L1 Q9NZQ7 0.026069 2_MASLD-1_HCV TNF-R1 * P19438 0.026383 3_MASH-2_MASLD Notch 3 Q9UM47 0.026546 2_MASLD-1_HCV; 3_MASH-1_HCV CD5 P06127 0.027523 2_MASLD-1_HCV CD6 P30203 0.027523 2_MASLD-1_HCV CSTB * P04080 0.028853 3_MASH-1_HCV; 3_MASH-2_MASLD uPA P00749 0.032758 2_MASLD-1_HCV AXL P30530 0.039458 2_MASLD-1_HCV PLC * P98160 0.04295 3_MASH-2_MASLD TFF3 Q07654 0.045234 2_MASLD-1_HCV Proteins with FDR-adjusted p-values of less than 0.05 for the one-way ANOVA test were listed. * indicates significant differences between MASLD and MASH within Cohort 2. # indicates that the significant difference observed in Cohort 1 was reproduced in Cohort 2. OPG1 was measured using both panels. Data from the CARDIOVASCULAR III panel for these proteins are indicated by a superscript "_c". Table 1-3. Proteins with differential levels among clinical categories in Cohort 3. Protein Uniprot ID FDR-adjusted p-value (BH) Tukey's HSD CASP-8 *# Q14790 4.97E-09 2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD SELE * P16581 4.59E-07 2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD IGFBP-2 P18065 4.69E-07 2_MASLD-1_HCV; 3_MASH-1_HCV TNFSF14 O43557 4.69E-07 2_MASLD-1_HCV; 3_MASH-1_HCV IGFBP-1 P08833 1.39E-06 2_MASLD-1_HCV; 3_MASH-1_HCV IL7 * P13232 1.58E-06 3_MASH-1_HCV; 3_MASH-2_MASLD LDL receptor P01130 1.63E-06 2_MASLD-1_HCV; 3_MASH-1_HCV FGF-21 Q9NSA1 1.75E-06 2_MASLD-1_HCV; 3_MASH-1_HCV OSM P13725 1.75E-06 2_MASLD-1_HCV; 3_MASH-1_HCV CASP-3 * P42574 2.25E-06 2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD TWEAK *# O43508 7.04E-06 3_MASH-1_HCV; 3_MASH-2_MASLD LAP TGF-beta-1 P01137 7.43E-06 2_MASLD-1_HCV; 3_MASH-1_HCV SELP P16109 2.33E-05 2_MASLD-1_HCV; 3_MASH-1_HCV CTSD *# P07339 2.34E-05 3_MASH-1_HCV; 3_MASH-2_MASLD PAI P05121 6.60E-05 2_MASLD-1_HCV; 3_MASH-1_HCV CXCL5 * P42830 6.90E-05 2_MASLD-1_HCV; 3_MASH-2_MASLD CXCL9 Q07325 0.0000768 2_MASLD-1_HCV; 3_MASH-1_HCV MMP-3 *# P08254 0.0000768 2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD PDGF subunit A * P04085 7.68E-05 2_MASLD-1_HCV; 3_MASH-2_MASLD PON3 * Q15166 7.68E-05 3_MASH-1_HCV; 3_MASH-2_MASLD SCF *# P21583 7.68E-05 3_MASH-1_HCV; 3_MASH-2_MASLD CHI3L1 * P36222 0.00011115 2_MASLD-1_HCV; 3_MASH-2_MASLD GP6 Q9HCN6 0.00013729 2_MASLD-1_HCV; 3_MASH-1_HCV MCP-3 * P80098 0.00014742 3_MASH-1_HCV; 3_MASH-2_MASLD MMP-9 P14780 0.00017729 2_MASLD-1_HCV; 3_MASH-1_HCV STAMBP O95630 0.00021226 2_MASLD-1_HCV; 3_MASH-1_HCV FABP4 * P15090 0.00030143 3_MASH-1_HCV; 3_MASH-2_MASLD TRAIL *# P50591 0.00035458 3_MASH-1_HCV; 3_MASH-2_MASLD OPG _ c O00300 0.00037758 2_MASLD-1_HCV; 3_MASH-1_HCV GDF-15 * Q99988 0.00038836 2_MASLD-1_HCV; 3_MASH-2_MASLD MPO P05164 0.00060826 2_MASLD-1_HCV; 3_MASH-1_HCV CCL16 O15467 0.00094184 2_MASLD-1_HCV; 3_MASH-1_HCV TFF3 Q07654 0.0011618 2_MASLD-1_HCV; 3_MASH-1_HCV TGF-alpha P01135 0.0011618 2_MASLD-1_HCV IL-1RT2 * P27930 0.0014993 3_MASH-1_HCV; 3_MASH-2_MASLD AZU1 P20160 0.0021148 2_MASLD-1_HCV; 3_MASH-1_HCV TRANCE O14788 0.0023726 2_MASLD-1_HCV; 3_MASH-1_HCV TLT-2 Q5T2D2 0.002569 2_MASLD-1_HCV; 3_MASH-1_HCV CCL23 * P55773 0.0026187 3_MASH-1_HCV; 3_MASH-2_MASLD EN-RAGE P80511 0.0038445 2_MASLD-1_HCV; 3_MASH-1_HCV OPG O00300 0.004438 2_MASLD-1_HCV; 3_MASH-1_HCV IL8 P10145 0.0054583 3_MASH-1_HCV CCL20 *# P78556 0.0060553 3_MASH-2_MASLD SCGB3A2 Q96PL1 0.0064909 2_MASLD-1_HCV; 3_MASH-1_HCV CDCP1 * Q9H5V8 0.0070516 2_MASLD-1_HCV; 3_MASH-2_MASLD CCL11 * P51671 0.0073257 3_MASH-1_HCV; 3_MASH-2_MASLD DNER * Q8NFT8 0.013792 2_MASLD-1_HCV; 3_MASH-2_MASLD Notch 3 Q9UM47 0.013792 2_MASLD-1_HCV; 3_MASH-1_HCV IL-18BP O95998 0.015443 2_MASLD-1_HCV TIMP4 Q99727 0.015443 3_MASH-1_HCV CPA1 P15085 0.015791 3_MASH-1_HCV TFPI * P10646 0.017396 3_MASH-1_HCV; 3_MASH-2_MASLD HGF P14210 0.01765 3_MASH-1_HCV ITGB2 * P05107 0.01987 3_MASH-1_HCV; 3_MASH-2_MASLD IFN-gamma P01579 0.024925 2_MASLD-1_HCV; 3_MASH-1_HCV CD93 Q9NPY3 0.028568 3_MASH-1_HCV MCP-2 * P80075 0.028568 2_MASLD-1_HCV; 3_MASH-2_MASLD IL2-RA P01589 0.028606 2_MASLD-1_HCV JAM-A Q9Y624 0.029976 3_MASH-1_HCV CCL28 Q9NRJ3 0.03836 3_MASH-1_HCV FGF-19 O95750 0.039581 3_MASH-1_HCV IL6 * P05231 0.039581 3_MASH-1_HCV; 3_MASH-2_MASLD EGFR P00533 0.042159 2_MASLD-1_HCV Gal-4 * P56470 0.043253 3_MASH-2_MASLD IGFBP-7 * Q16270 0.043253 3_MASH-2_MASLD uPA P00749 0.047227 2_MASLD-1_HCV Proteins with FDR-adjusted p-values of less than 0.05 for the one-way ANOVA test were listed. * indicates significant differences between MASLD and MASH within Cohort 3. # ndicates significant differences between MASLD and MASH, reproduced across all three cohorts (Figures 2a-2g). OPG1 was measured using both panels. Data from the CARDIOVASCULAR III panel for these proteins are indicated by a superscript "_c". Targeted Lipidomics In Cohort 2 and Cohort 3, targeted phospholipids analysis was performed and revealed significant differences in 131 phospholipid species in Cohort 2 (Table S5-1) and in 129 phospholipid species in Cohort 3 (Table S5-2), 47 of which showed significant differences between MASLD and MASH in Cohort 2 (Table S5-1) and 49 in Cohort 3 (Table S5-2). Among these, 29 phospholipids demonstrated reproducibility (Table 2). Of these 29, 12 species were identified as diradyl (with two fatty chains) PE, including seven species with an ether bond of which five were presumed to have a vinyl-ether bond. Examining the 12 PEs that showed significant alterations in either Cohort 2 or Cohort 3, all seven ether PEs were significantly decreased in MASH compared to MASLD. PEs with two ester bonds, on the other hand, were significantly increased in MASH compared to those in MASLD in both Cohort 2 and Cohort 3 (Figure 2). Table 2. Phospholipids with differential levels reproduced in Cohort 2 and Cohort 3 between MASLD and MASH. Lipid Name Lipid Class FDR-adjusted p-value (BH) Cohort 2 FDR-adjusted p-value (BH) Cohort 3 Tukey's HSD Cohort 2 Tukey's HSD Cohort 3 LPC_18:2 PC 3.88E-02 2.07E-02 3_MASH-2_MASLD 2_MASLD-1_HCV; 3_MASH-2_MASLD LPC_18:2_FA_18:2 PC 3.22E-02 3.12E-02 3_MASH-2_MASLD 3_MASH-2_MASLD LPC_24:0 PC 1.08E-03 3.60E-02 3_MASH-1_HCV; 3_MASH-2_MASLD 3_MASH-1_HCV; 3_MASH-2_MASLD PC_18:2_20:4_FA_18:2 PC 1.24E-02 3.37E-02 2_MASLD-1_HCV; 3_MASH-2_MASLD 3_MASH-2_MASLD PC_33:1 PC 1.89E-02 3.16E-03 2_MASLD-1_HCV; 3_MASH-2_MASLD 2_MASLD-1_HCV; 3_MASH-2_MASLD PC_36:1 PC 1.08E-03 2.57E-03 3_MASH-1_HCV; 3_MASH-2_MASLD 3_MASH-1_HCV; 3_MASH-2_MASLD PC_O-34:2_FA_18:2 PC 4.41E-03 3.16E-03 3_MASH-1_HCV; 3_MASH-2_MASLD 3_MASH-1_HCV; 3_MASH-2_MASLD PC_O-34:2_peak1 PC 1.08E-03 5.47E-03 3_MASH-1_HCV; 3_MASH-2_MASLD 3_MASH-1_HCV; 3_MASH-2_MASLD PC_O-34:3 PC 2.25E-03 4.20E-04 3_MASH-1_HCV; 3_MASH-2_MASLD 3_MASH-1_HCV; 3_MASH-2_MASLD PC_O-36:2 PC 3.14E-02 1.84E-02 3_MASH-1_HCV; 3_MASH-2_MASLD 3_MASH-1_HCV; 3_MASH-2_MASLD PC_O-36:2_FA_18:2 PC 3.15E-02 5.28E-03 3_MASH-1_HCV; 3_MASH-2_MASLD 3_MASH-1_HCV; 3_MASH-2_MASLD PC_O-36:3 PC 7.44E-03 3.35E-03 3_MASH-1_HCV; 3_MASH-2_MASLD 3_MASH-1_HCV; 3_MASH-2_MASLD PC_O-38:5 PC 2.33E-02 2.97E-02 3_MASH-1_HCV; 3_MASH-2_MASLD 3_MASH-1_HCV; 3_MASH-2_MASLD LPE_20:4 PE 4.74E-02 9.62E-03 2_MASLD-1_HCV; 3_MASH-2_MASLD 2_MASLD-1_HCV; 3_MASH-2_MASLD PE_16:0_22:6_FA_16:0 PE 2.23E-02 1.84E-02 3_MASH-1_HCV; 3_MASH-2_MASLD 3_MASH-1_HCV; 3_MASH-2_MASLD PE_18:0_22:6_FA_18:0 PE 9.66E-04 4.94E-03 3_MASH-1_HCV; 3_MASH-2_MASLD 3_MASH-1_HCV; 3_MASH-2_MASLD PE_34:1 PE 3.22E-02 6.87E-03 3_MASH-1_HCV; 3_MASH-2_MASLD 3_MASH-2_MASLD PE_38:6 PE 2.23E-02 9.91E-03 2_MASLD-1_HCV; 3_MASH-2_MASLD 2_MASLD-1_HCV; 3_MASH-2_MASLD PE_40:6 PE 3.09E-03 1.09E-02 3_MASH-1_HCV; 3_MASH-2_MASLD 3_MASH-1_HCV; 3_MASH-2_MASLD PE_O-38:5_FA_22:5 PE 2.34E-02 4.18E-02 3_MASH-2_MASLD 3_MASH-2_MASLD PE_O-40:6_FA_22:5 PE 4.66E-03 3.16E-03 2_MASLD-1_HCV; 3_MASH-2_MASLD 2_MASLD-1_HCV; 3_MASH-2_MASLD PE_O-38:6_FA_22:5 PE 9.55E-04 2.57E-03 2_MASLD-1_HCV; 3_MASH-2_MASLD 2_MASLD-1_HCV; 3_MASH-2_MASLD PE_P-16:0_22:5 PE 4.78E-03 2.57E-03 2_MASLD-1_HCV; 3_MASH-2_MASLD 2_MASLD-1_HCV; 3_MASH-2_MASLD PE_P-18:0_22:5 PE 1.46E-02 3.16E-03 2_MASLD-1_HCV; 3_MASH-2_MASLD 2_MASLD-1_HCV; 3_MASH-2_MASLD PE_P-18:1_22:4 PE 2.42E-02 3.16E-02 2_MASLD-1_HCV; 3_MASH-2_MASLD 3_MASH-2_MASLD PE_P-18:1_22:5 PE 1.24E-02 1.18E-02 2_MASLD-1_HCV; 3_MASH-2_MASLD 2_MASLD-1_HCV; 3_MASH-2_MASLD SM_36:0;O2 SM 9.55E-04 1.36E-03 3_MASH-1_HCV; 3_MASH-2_MASLD 3_MASH-1_HCV; 3_MASH-2_MASLD SM_38:0;O2 SM 3.46E-04 8.20E-04 3_MASH-1_HCV; 3_MASH-2_MASLD 3_MASH-1_HCV; 3_MASH-2_MASLD Phospholipids with an FDR-adjusted p-value of less than 0.05 for the one-way ANOVA test and showed significant change with Tukey’s HSD post hoc test between MASH and MASLD were listed. All detected PE species are displayed in a volcano plot, and most components with ether bonds were observed to exhibit low values in the MASH (Figure 2e). Among the 17 phospholipids other than PE, 10 were diradyl phosphatidylcholine (PC), four were lyso PC or lyso PE, and three were saturated sphingomyelin (SM). Similar to PE, ether-linked PC was also found to be lower in MASH (Figure 2f). The trend of lower and higher levels in ether and diacyl lipids in MASH, however, appears to be more pronounced in PE than in PC. The ether-linked phospholipids for which reproducible changes were observed contained two or more unsaturated bonds. Regarding SMs, three SMs with saturated fatty acids were increased in MASH compared to MASLD (Figure 2c). The four lyso PLs were all lower in MASH (Figure 2d). For HCV, 85 phospholipid molecules showed significant differences in both Cohort 2 and Cohort 3 (Observed differences between HCV and MASLD or MASH in both cohorts are indicated by a “†” in Table S5-1 and Table S5-2). Among these, 17 phospholipid molecules exhibited significant difference in both Cohort 2 and Cohort 3 between HCV and MASLD and also between HCV and MASH (Table 3), though no changes were observed for MASLD and MASH (excluding one SM that changed significantly in only one cohort). They included eight SM and six PC components; since Table 3. Phospholipids with differential levels in HCV reproduced in Cohort 2 and Cohort 3. Lipid Name Lipid Class FDR-adjusted p-value (BH) Cohort 2 FDR-adjusted p-value (BH) Cohort 3 Tukey's HSD Cohort 2 Tukey's HSD Cohort 3 LPC_22:6 PC 1.24E-02 1.18E-02 2_MASLD-1_HCV; 3_MASH-1_HCV 2_MASLD-1_HCV; 3_MASH-1_HCV PC_38:3 PC 2.25E-03 1.47E-02 2_MASLD-1_HCV; 3_MASH-1_HCV 2_MASLD-1_HCV; 3_MASH-1_HCV PC_O-32:1 PC 3.70E-02 1.55E-03 2_MASLD-1_HCV; 3_MASH-1_HCV 2_MASLD-1_HCV; 3_MASH-1_HCV PC_O-34:1 PC 2.17E-02 9.48E-03 2_MASLD-1_HCV; 3_MASH-1_HCV 2_MASLD-1_HCV; 3_MASH-1_HCV PC_O-34:2_FA_18:1 PC 1.46E-02 3.16E-03 2_MASLD-1_HCV; 3_MASH-1_HCV 2_MASLD-1_HCV; 3_MASH-1_HCV PC_O-34:2_peak2 PC 1.46E-02 2.34E-03 2_MASLD-1_HCV; 3_MASH-1_HCV 2_MASLD-1_HCV; 3_MASH-1_HCV PC_O-36:2_FA_18:1_peak1 PC 3.79E-02 3.16E-03 2_MASLD-1_HCV; 3_MASH-1_HCV 2_MASLD-1_HCV; 3_MASH-1_HCV PI_18:0_18:2_FA_18:2 PI 2.03E-05 8.20E-04 2_MASLD-1_HCV; 3_MASH-1_HCV 2_MASLD-1_HCV; 3_MASH-1_HCV PI_36:2 PI 7.92E-05 6.87E-03 2_MASLD-1_HCV; 3_MASH-1_HCV 2_MASLD-1_HCV; 3_MASH-1_HCV SM_34:0;O2 SM 6.80E-04 6.55E-04 2_MASLD-1_HCV; 3_MASH-1_HCV 2_MASLD-1_HCV; 3_MASH-1_HCV SM_35:2;O2 SM 2.48E-02 3.83E-03 2_MASLD-1_HCV; 3_MASH-1_HCV 2_MASLD-1_HCV; 3_MASH-1_HCV SM_36:1;O2 SM 1.50E-06 1.39E-07 2_MASLD-1_HCV; 3_MASH-1_HCV 2_MASLD-1_HCV; 3_MASH-1_HCV SM_36:2;O2 SM 1.13E-06 1.39E-07 2_MASLD-1_HCV; 3_MASH-1_HCV 2_MASLD-1_HCV; 3_MASH-1_HCV SM_38:1;O2 SM 1.91E-08 9.26E-08 2_MASLD-1_HCV; 3_MASH-1_HCV 2_MASLD-1_HCV; 3_MASH-1_HCV SM_40:1;O2 SM 3.77E-07 2.34E-04 2_MASLD-1_HCV; 3_MASH-1_HCV 2_MASLD-1_HCV; 3_MASH-1_HCV SM_40:2;O2 SM 1.53E-09 1.39E-07 2_MASLD-1_HCV; 3_MASH-1_HCV 2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD SM_40:3;O2 SM 1.54E-02 5.40E-03 2_MASLD-1_HCV; 3_MASH-1_HCV 2_MASLD-1_HCV; 3_MASH-1_HCV Phospholipids with an FDR-adjusted p-value of less than 0.05 for the one-way ANOVA test and showed siginificant change with Tukey's HSD post hoc test between HCV and MASLD or HCV and MASH. SM has fewer components as targets in this lipidomics research than PC due to the lower variety of SM species in plasma, we conclude that a larger proportion of SMs accounted for the altered lipids in HCV compared to MASH and MASLD (35 targeted features for SMs and 204 targeted features for PCs). Next, targeted TG analysis was conducted. In Cohort 2, 26 TG species had an FDR-adjusted p-value smaller than 0.1 (raw p value < 0.02) by ANOVA (Table S6-1), among which 18 TGs marked with an asterisk ( * ) in Table S6-1 exhibited significant differences between MASLD and MASH. To confirm reproducibility, TG analysis was performed in Cohort 3, and differences in 27 TG species (Table S6-2) were identified. Results showed 14 species indicated with an asterisk ( * ) in Table S6-2 with differences between MASLD and MASH. Eight TG species marked with ( # ) in Table S6-1 and Table S6-2 showed proof and reproducible differences between MASLD and MASH across both Cohort 2 and Cohort 3 (Table 4, Fig 3). Of those eight TG molecular species, five contained 18:2 fatty chains. Of note, all five of the 18:2-containing TG components were lower abundance in MASH than in MASLD. The patterns of low level of 18:2 fatty acyl chain containing TG in MASH were confirmed by a volcano plot of both Cohort 2 and Cohort 3 (Fig S3). To detect characteristics of HCV against MASH or MAFLD, we also listed TG components that were different by ANOVA but not between MASH and MASLD (Table S7, Figure S4). Correlations for protein-to-lipid interaction between the proteins that showed significant variation across the three cohorts and the lipids that exhibited changes in Cohort 2 and Cohort 3 (Table S8) were analyzed. Of the seven proteins (CASP-8, CCL20, CTSD, MMP-3, SCF, TRAIL, and TWEAK) that showed good reproducible changes between MASLD and MASH, CTSD in particular correlated with several PEs: positively with two diacyl PEs and negatively with six ether PEs (Fig S5). In addition, CTSD showed a negative correlation with five TGs containing FA18:2 (Fig S5). Thus, CTSD predominantly correlated with lipids that characterized MASH with lipidomic results. CCL20 also showed a similar trend (one diacyl PE, three ether PEs, two TGs containing FA18:2) although it did not correlate with as many lipids as CTSD. MMP3 was characterized by a negative correlation with PE with FA22:6. For SCF, a negative correlation with lipids having mono-unsaturation was characteristic. Three mono-saturated phospholipids and one TG with mono-saturated fatty acids all showed a negative correlation with SCF (Table S8). Table 4. Triglycerides reproduced in Cohort 2 and Cohort 3 with differential levels between MASLD and MASH. Lipid Name p-value Cohort 2 p-value Cohort 3 FDR-adjusted p-value (BH) Cohort 2 FDR-adjusted p-value (BH) Cohort 3 Tukey's HSD Cohort 2 Tukey's HSD Cohort 3 TG Name Species level Containing fatty chain TG_50:2-FA_18:1 1.53E-02 2.04E-02 0.0990 0.0999 2_MASLD-1_HCV; 3_MASH-2_MASLD 3_MASH-2_MASLD TG_50:2 FA_18:1 TG_52:3-FA_16:0 7.41E-03 6.87E-03 0.0956 0.0612 2_MASLD-1_HCV; 3_MASH-2_MASLD 3_MASH-2_MASLD TG_52:3 FA_16:0 TG_52:3-FA_18:2 1.22E-02 3.63E-03 0.0990 0.0612 3_MASH-2_MASLD 3_MASH-2_MASLD TG_52:3 FA_18:2 TG_52:4-FA_16:0 7.18E-03 1.41E-03 0.0956 0.0373 3_MASH-2_MASLD 3_MASH-1_HCV; 3_MASH-2_MASLD TG_52:4 FA_16:0 TG_52:4-FA_18:2 9.05E-03 1.30E-03 0.0956 0.0373 3_MASH-2_MASLD 3_MASH-1_HCV; 3_MASH-2_MASLD TG_52:4 FA_18:2 TG_52:5-FA_18:2 7.54E-03 3.48E-03 0.0956 0.0612 3_MASH-2_MASLD 3_MASH-1_HCV; 3_MASH-2_MASLD TG_52:5 FA_18:2 TG_54:5-FA_18:2 4.69E-03 1.38E-03 0.0956 0.0373 3_MASH-1_HCV; 3_MASH-2_MASLD 3_MASH-1_HCV; 3_MASH-2_MASLD TG_54:5 FA_18:2 TG_54:6-FA_18:2 1.01E-02 1.29E-03 0.0956 0.0373 3_MASH-1_HCV; 3_MASH-2_MASLD 3_MASH-1_HCV; 3_MASH-2_MASLD TG_54:6 FA_18:2 Triglyderides with FDR-adjusted p-values of less than 0.05 for the one-way ANOVA test and which showed siginificant change with Tukey`s HSD post hoc test between MASH and MASLD or HCV and MASH in both Cohort 2 and Cohort 3 were listed. 4. Discussion The relationship between each protein and lipid molecule for the results obtained in this study is shown in Fig. 4 (related molecules are connected to each other by lines). CASP-8 is a crucial enzyme to initiating apoptosis via the extrinsic pathway mediated by DR4 and DR5 that serves as the starting point. In MASH, hepatocyte apoptosis increases, and CASP-8 activation contributes to the progression of liver inflammation and fibrosis 16 , 17 . Similarly, in HCV infection, cellular stress associated with viral replication activates CASP-8, inducing hepatocyte apoptosis. HCV-mediated apoptosis by CASP-8 also contributes to chronic inflammation by releasing apoptotic debris. However, some reports suggest that HCV modulates CASP-8 activity to delay apoptosis and prefer viral persistence, however, this mechanism remains unclear 18 . The chemokine CCL20 recruits CCR6-expressing immune cells, and becomes elevated in MASH liver tissue. This, in turn, intensifies inflammatory responses and immune cell infiltration 19 . In HCV infection, antigen presentation activates immune cells and upregulates CCL20, further aggravating inflammation. The correlation between CASP-8 and CCL20 expression suggests that apoptotic signals induce CCL20 secretion, exacerbating inflammation even further. Persistent CCL20 elevation in chronic HCV infection likely contributes to excessive immune infiltration and fibrosis, though its mechanistic role is still under investigation 20 . The lysosomal enzyme CTSD is involved in protein degradation and autophagy, and increases as MASLD progresses to MASH, a sign of enhanced cellular stress responses 21 . The significant correlation between CCL20 and CTSD expression implies that macrophage activation and lysosomal function modulation associated with inflammation are involved. In HCV infection, viral replication alters lysosomal function, potentially modulating CTSD expression and supporting viral persistence, all of which must be investigated further. The MMP-3 enzyme is involved in extracellular matrix (ECM) remodeling and decreased in MASH, potentially promoting ECM accumulation and fibrosis 22 . MMP-3 also affects lipid metabolism through adipocyte remodeling and inflammation regulation 23 . The observed reductions in MMP-3, SCF, TRAIL, and TWEAK suggest the presence of damaged liver repair and immune clearance mechanisms that encourage fibrosis progression. The growth factor SCF regulates hematopoietic and hepatic stem cells 24 – 26 , and typically increases with early injury or stress, as in MASLD cases where SCF-producing cells decline. As a result, regenerative capacity is diminished. Reduced SCF in a fibrotic, inflammatory environment can prevent liver repair. The TRAIL protein induces apoptosis by binding to DR4 and DR5 receptors 27 , was decreased in MASH, indicating reduced immune clearance of hepatocytes. In HCV infection, TRAIL expression is variable but can influence hepatocyte injury and clearance 28 . TWEAK protein regulates cell survival, differentiation, and apoptosis via the Fn14 receptor 29 . These levels were elevated in MASH, signifying involvement in hepatocyte injury and fibrosis progression. Both TRAIL and TWEAK are members of the tumor necrosis factor (TNF) superfamily involved in apoptosis regulation 30 , 31 . Their concurrent downregulation in MASH suggests a reduction in immune cell-mediated hepatocyte clearance, all of which contribute to chronic inflammation. The significant correlation between TRAIL and TWEAK expression implies a coordinated regulatory mechanism in hepatic immune responses. In MASH, ether-linked PE (PE O (1-O-alkyl-2-acyl-sn-glycero-3-phosphoethanolamine), PE P (1-O-(1'Z-alkenyl)-2-acyl-sn-glycero-3-phosphoethanolamine, plasmalogen) is reduced, whereas ester-linked PE is increased. These shifts driven by oxidative stress and peroxisomal dysfunction 32 , may increase membrane vulnerability to lipid peroxidation 33 , promote apoptosis, and destabilize membrane homeostasis 34 . Sphingomyelins (SM) containing saturated fatty acids that rigidify lipid rafts 35 . SMs increased in MASH, which contribute a strong resistance to insulin. 36 . Conversely, unsaturated SM (SM_38:2, SM_40:2) is elevated in MASLD, indicating lipid metabolism alterations. On the one hand, the number of TG species containing linoleic acid (18:2) diminished in MASH, likely because of increased β-oxidation or prevented VLDL incorporation. TGs containing DHA or AA, on the other hand, were maintained, likely reflecting their essential structural roles. The CTSD protein showed a positive correlation with TGs containing linoleic acid, suggesting a role in lipid turnover 37 . In advanced stages of a chronic disease, lysosomal dysfunction may reduce lipid degradation 38 , which alters TG homeostasis. SCF correlated inversely with monounsaturated fatty acid (MUFA)-containing lipids across Cohort 2 and Cohort 3, consistent with compensatory increases in anti-inflammatory MUFAs 39 , 40 , that attenuate SCF/c-Kit signaling by modifying membrane lipid raft composition 41 . This suggests a lipid-mediated feedback mechanism modulating SCF activity during chronic injury. Although correlations between CCL20 and lipid species were less consistent, inverse associations with ether-type PE and TGs containing linoleic acid were observed in both Cohorts 2 and Cohort 3, suggesting interaction occurs. No reproducible lipid correlations were identified for CASP-8, TRAIL, or TWEAK. Furthermore, this large-scale dual-omics analysis performed exclusively on Japanese patients provides population-specific insights that complement existing data from non-Japanese cohorts, and highlight the need for diverse datasets to advance biomarker discovery and precision medicine in chronic liver diseases. 5. Conclusion Our study highlights molecular features associated with MASH and HCV infection, especially in apoptosis, immune response, and lipid metabolism. CASP-8 activation, together with CCL20, points to apoptotic signals that likely drive immune cell recruitment and chronic inflammation. Lipid alterations in MASH, the reduction of ether-linked PE, and the increase in ester-linked PE and saturated SM all suggest a shift in membrane composition affecting insulin signaling and oxidative stress resistance. The accumulation of linoleic acid-containing TGs seems to exacerbate inflammation and fibrosis by promoting eicosanoid production. The inverse correlation between CCL20 and ether-linked PE or linoleic acid-containing TGs indicates a potential interaction between immune signaling and lipid metabolism. SCF regulates hematopoietic and hepatic stem cells, and shows a negative relationship with MUFA containing lipids. This is likely related to feedback regulation within an injured liver. CTSD, a lysosomal enzyme involved in protein and lipid degradation, inversely correlates with linoleic acid-containing TGs, revealing a potential role in lipid turnover important for regulating body weight and metabolic health. The roles of CASP-8, TRAIL, and TWEAK in apoptosis and fibrosis are known, and showed no reproducible correlations with lipid species. This suggests that their primary functions in MASH and HCV pathogenesis are likely independent of lipid alterations. These findings should be regarded as hypothesis-generating and reference-quality, offering reproducible proteomic and lipidomic data from several hundred Japanese patients. Rather than establishing definitive diagnostic biomarkers or mechanisms, this framework provides a valuable resource to guide future studies in risk stratification, therapeutic monitoring, and mechanistic validation across broader populations. Abbreviations CASP-8, caspase-8; CCL20, C-C motif chemokine ligand 20; CTSD, cathepsin D; ECM, extracellular matrix; FA, fatty acid; FDR, false discovery rate; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LC/MS, liquid chromatography/mass spectrometry, MASH, metabolic dysfunction-associated steatohepatitis; MASLD, metabolic dysfunction-associated steatotic liver disease; MMP-3, matrix metalloproteinase-3; MUFA, monounsaturated fatty acid; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PEA, proximity extension assay; PL, phospholipid; QC, quality control; qPCR, quantitative polymerase chain reaction; SCF, stem cell factor; SM, sphingomyelin; SRM, selected reaction monitoring; TG, triglyceride; TNF, tumor necrosis factor; TRAIL, tumor necrosis factor -related apoptosis-inducing ligand; TWEAK, tumor necrosis factor-related weak inducer of apoptosis; VLDL, very low-density lipoproteins. Declarations ACKNOWLEDGMENTS We would like to express our gratitude to the study participants and all the investigators involved in the study. We are deeply grateful to Dr. Tohru Natsume and members of Robotic Biology Institute Inc. (RBI) for providing us with a humanoid robot Maholo to improve accurate sample handlings. We thank Yoshihiro Kita and Hatsue Igarashi for their assistance. We would like to express our appreciation to Masaki Yamada for his contribution to the creation of our lipidomics methods. Author Contributions Y.O. conceived and supervised the project and wrote the manuscript. S.M.T. was responsible for lipidomics analyses and preparation of figures and tables. F.H. and A.K. conducted the proteomics experiments. M.S., H.T., and M.M. were in charge of the collection and storage management of clinical specimens. Funding This research was supported by AMED (23tm0624002j0001), AMED (243fa627011h003) and AMED (24ae0121041s0104) (to Y.O.) and JSPS KAKENHI (21K06853) (to S.M.T.). The Department of Lipidomics is supported by the Shimadzu Corporation. Data Availability Statement The mass spectrometry data have been deposited to Zenodo (Accession Number: 10.5281/zenodo.15736637). Ethics approval This study received approval from the Research Ethics Committee of the Faculty of Medicine of the University of Tokyo (Approval numbers 2019282NI-(2), 2019283NI-(2), and 2019022NI). Consent for publication Not applicable. Competing interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 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Supplementary Files supplementaryTablesSMTokuoka2500922.xlsx Table S1: Subject demographic characteristics Table S2: MRM transitions for phospholipid measurements Table S3: MRM transitions for TG measurements Table S4: Protein-to-protein correlations Table S5-1: Phospholipids with differential levels among clinical categories in Cohort 2 Table S5-2: Phospholipids with differential levels among clinical categories in Cohort 3 Table S6-1: Triglycerides with differential levels among clinical categories in Cohort 2 Table S6-2: Triglycerides with differential levels among clinical categories in Cohort 3 Table S7: Triglycerides with differential levels in HCV reproduced in Cohort 2 and Cohort 3 Table S8: Protein-lipid correlations Table S9: Individual Subject Information Table S10: Data for Proteomics (NPX) Table S11: Data for Lipidomics-phospholipids Table S12: Data for Lipidomics-triglycerides supplementaryFigsSMTokuoka250922.pdf Supporting Information Figure S1: Protein-to-protein correlations. Among the seven proteins that showed changes between MASH and MASLD reproducibly in all three cohorts, those that were significantly correlated with each other with Pearson's correlation value R of more than 0.2 were plotted. Light blue dots indicate HCV, green MASLD and red MASH; X- and Y-axes indicate protein expression levels with NPX values. The dots represent each data point. The dot colors indicate clinical category of the samples. Blue dots represent HCV, green dots represent MASLD, and red dots indicate MASH. Figure S2: Sphingomyelins (SMs) with differential levels between HCV and MASH. Horizontal lines in the rectangle represent the median, boxes represent the interquartile range, and whiskers represent the 5th and 95th percentiles. The dots represent each data point. Figure S3: Volcano plots showing differences in TG levels among clinical categories. Each dot represents 132 features for TG 18 of which TG features containing FA 18:2 are colored yellow. The X-axis represents the log2 fold change between clinical categories. The Y-axis represents the p-value by two-tailed Student’s t-test (value of −log10). Figure S4: Triglycerides (TGs) with differential levels reproduced in Cohort 2 and Cohort 3 among HCV to MASH or MASLD. The lipids exhibited significant variances in one-way ANOVA test following FDR multiple testing correction and Tukey‘s HSD test between HCV and MASLD or MASH (see Table S7). Horizontal lines in the rectangles represent the median, boxes represent the interquartile range, and whiskers represent the 5th and 95th percentiles. The dots represent each data point. Figure S5: CTSD-to-Lipid correlations. Pearson's correlation analysis showed a significant correlation between CTSD to lipids reproducibly altered level in MASH as shown in Table S8. Among them, the correlations for PE and TG and CTSD, which are well characterized in MASH, are shown in the plots. The dots represent each data point. The dot colors indicate clinical category of the samples. Blue dots represent HCV, green dots represent MASLD and red dots indicate MASH. Cite Share Download PDF Status: Published Journal Publication published 11 Feb, 2026 Read the published version in Clinical Proteomics → Version 1 posted Editorial decision: Revision requested 30 Dec, 2025 Reviews received at journal 15 Dec, 2025 Reviewers agreed at journal 02 Dec, 2025 Reviewers agreed at journal 03 Oct, 2025 Reviews received at journal 29 Sep, 2025 Reviewers agreed at journal 28 Sep, 2025 Reviewers invited by journal 28 Sep, 2025 Editor assigned by journal 23 Sep, 2025 Submission checks completed at journal 23 Sep, 2025 First submitted to journal 22 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7675910","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":526694331,"identity":"bf2476cd-947c-434f-828b-cc51d3513188","order_by":0,"name":"Suzumi M Tokuoka","email":"","orcid":"","institution":"The University of Tokyo","correspondingAuthor":false,"prefix":"","firstName":"Suzumi","middleName":"M","lastName":"Tokuoka","suffix":""},{"id":526694332,"identity":"f8fa8bd2-ebc9-47a7-b830-052a84476bda","order_by":1,"name":"Fumie Hamano","email":"","orcid":"","institution":"The University of 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1","display":"","copyAsset":false,"role":"figure","size":191563,"visible":true,"origin":"","legend":"\u003cp\u003eProteins with differential levels reproduced in all three Cohorts between MASLD and MASH. Level of proteins CASP-8 (a), CCL20 (b), CTSD (c), MMP-3 (d), SCF (e), TRAIL (f), TWEAK (g) in plasma samples in each cohort. The proteins exhibited significant variances by two-tailed Student’s t-test (in Cohort 1) or one-way ANOVA test (in Cohort 2 and Cohort 3) following FDR multiple testing correction and between MASH and MASLD in Tukey's HSD (Honestly Significant Difference) test. Horizontal lines in the rectangles represent the median, boxes represent the interquartile range, and whiskers represent the 5th and 95th percentiles. The dots represent each data point.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7675910/v1/2434fda8d0c0d33389e83490.png"},{"id":93252894,"identity":"d45f031c-13a3-4036-a9c7-af2229ce0821","added_by":"auto","created_at":"2025-10-10 16:04:29","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":197264,"visible":true,"origin":"","legend":"\u003cp\u003ePhospholipids with differential levels between MASLD and MASH. Levels of diradyl PE(a), diradyl PC(b), SM(c), lyso-phospholipid(d). The lipids exhibited significant variances in one-way ANOVA test following FDR multiple testing correction, and between MASH and MASLD in Tukey‘s HSD test (see Table 2). Horizontal lines in the rectangles represent the median, boxes represent the interquartile range, and whiskers represent the 5th and 95th percentiles. The dots represent each data point. Volcano plot for PEs displays 123 features (e), of which 58 are ether species. Volcano plots for PCs displays 204 features (f), of which 32 are ether species. The X-axis represents the log2 fold change between MASH and MASLD. The Y-axis represents the FDR-adjusted p-value by two-tailed Student’s t-test (value of −log10). The blue dots represent ether phospholipids.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7675910/v1/15cd9aa7c0a1cc26d86cf41c.png"},{"id":93251511,"identity":"ca2089e2-59cc-4015-bb6c-f5bf3f773f53","added_by":"auto","created_at":"2025-10-10 15:48:29","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":190898,"visible":true,"origin":"","legend":"\u003cp\u003eTGs with differential levels reproduced in Cohort 2 and Cohort 3 between MASLD and MASH. The lipids exhibited significant variances in one-way ANOVA test following FDR multiple testing correction and Tukey‘s HSD test and between MASH and MASLD (see Table S5-1, Table S5-2, and Table 4). Horizontal lines in the rectangles represent the median, boxes represent the interquartile range, and whiskers represent the 5th and 95th percentiles. The dots represent each data point.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7675910/v1/94247c3e21d185c27a3bf6e3.png"},{"id":93251509,"identity":"9d553b31-bf8b-40a2-9d1f-7736257814db","added_by":"auto","created_at":"2025-10-10 15:48:29","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":136487,"visible":true,"origin":"","legend":"\u003cp\u003eRelationships between molecules associated with liver inflammation and fibrosis progression. This schematic diagram shows the molecular interactions and correlations between the proteins and lipid species that were the focus of this study. Increased CASP-8 expression promotes apoptosis, leading to elevated CCL20 levels, which in turn enhances immune cell recruitment and chronic inflammation, further accelerating fibrosis progression. Increased levels of ester-linked PE and saturated SM causes elevated membrane rigidity and damaging lipid metabolism. This leads to a decrease in ether- bound PE, which accompanies disrupted insulin signaling, reduced oxidative stress resistance, upregulation of CTSD, and promotion of apoptosis. CTSD expression accompanies a decrease in linoleic acid-containing TG. Increased membrane rigidity leads to a drop in SCF, a decrease in MUFA-containing lipids, and to reductions in TRAIL and TWEAK. When combined with a lower level of MMP3, it contributes to the progression of fibrosis by obstructing liver tissue maintenance and abnormal cell removal. The orange boxes indicate the starting points of identifying biomarkers of reactions, the thick black box indicates the final phenotype, and the thick lines indicate significant correlations or inverse correlations. The legend indicates the direction of molecular changes (↑ increase, ↓ decrease, △alteration).\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7675910/v1/8d8dbc0d2a4078e39980ca85.png"},{"id":102785323,"identity":"a419cc48-3da0-4130-b14e-c7a66cd2651e","added_by":"auto","created_at":"2026-02-16 16:05:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1787371,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7675910/v1/fcd2d113-7a84-4d17-b406-46a5c1d22575.pdf"},{"id":93252535,"identity":"fccc8e66-d25b-4972-94ba-e9e444901a84","added_by":"auto","created_at":"2025-10-10 15:56:29","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":3119545,"visible":true,"origin":"","legend":"\u003cp\u003eTable S1: \u0026nbsp;Subject demographic characteristics\u003c/p\u003e\n\u003cp\u003eTable S2: \u0026nbsp;MRM transitions for phospholipid measurements\u003c/p\u003e\n\u003cp\u003eTable S3: \u0026nbsp;MRM transitions for TG measurements\u003c/p\u003e\n\u003cp\u003eTable S4: Protein-to-protein correlations\u003c/p\u003e\n\u003cp\u003eTable S5-1: Phospholipids with differential levels among clinical categories in Cohort 2\u003c/p\u003e\n\u003cp\u003eTable S5-2: Phospholipids with differential levels among clinical categories in Cohort 3\u003c/p\u003e\n\u003cp\u003eTable S6-1: Triglycerides with differential levels among clinical categories in Cohort 2\u003c/p\u003e\n\u003cp\u003eTable S6-2: Triglycerides with differential levels among clinical categories in Cohort 3\u003c/p\u003e\n\u003cp\u003eTable S7: Triglycerides with differential levels in HCV reproduced in Cohort 2 and Cohort 3\u003c/p\u003e\n\u003cp\u003eTable S8: Protein-lipid correlations\u003c/p\u003e\n\u003cp\u003eTable S9: Individual Subject Information\u003c/p\u003e\n\u003cp\u003eTable S10: Data for Proteomics (NPX)\u003c/p\u003e\n\u003cp\u003eTable S11: Data for Lipidomics-phospholipids\u003c/p\u003e\n\u003cp\u003eTable S12: Data for Lipidomics-triglycerides\u003c/p\u003e","description":"","filename":"supplementaryTablesSMTokuoka2500922.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7675910/v1/25b581d8e7f6b4dd0cd0d2ca.xlsx"},{"id":93252537,"identity":"64eee85a-1582-4253-bca3-b39118037f35","added_by":"auto","created_at":"2025-10-10 15:56:29","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":796059,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupporting Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure S1: Protein-to-protein correlations. Among the seven proteins that showed changes between MASH and MASLD reproducibly in all three cohorts, those that were significantly correlated with each other with Pearson's correlation value R of more than 0.2 were plotted. Light blue dots indicate HCV, green MASLD and red MASH; X- and Y-axes indicate protein expression levels with NPX values. The dots represent each data point. The dot colors indicate clinical category of the samples. Blue dots represent HCV, green dots represent MASLD, and red dots indicate MASH.\u003c/p\u003e\n\u003cp\u003eFigure S2: Sphingomyelins (SMs) with differential levels between HCV and MASH. Horizontal lines in the rectangle represent the median, boxes represent the interquartile range, and whiskers represent the 5th and 95th percentiles. The dots represent each data point.\u003c/p\u003e\n\u003cp\u003eFigure S3: Volcano plots showing differences in TG levels among clinical categories. Each dot represents 132 features for TG 18 of which TG features containing FA 18:2 are colored yellow. The X-axis represents the log2 fold change between clinical categories. The Y-axis represents the p-value by two-tailed Student’s t-test (value of −log10).\u003c/p\u003e\n\u003cp\u003eFigure S4: Triglycerides (TGs) with differential levels reproduced in Cohort 2 and Cohort 3 among HCV to MASH or MASLD. The lipids exhibited significant variances in one-way ANOVA test following FDR multiple testing correction and Tukey‘s HSD test between HCV and MASLD or MASH (see Table S7). Horizontal lines in the rectangles represent the median, boxes represent the interquartile range, and whiskers represent the 5th and 95th percentiles. The dots represent each data point.\u003c/p\u003e\n\u003cp\u003eFigure S5: CTSD-to-Lipid correlations. Pearson's correlation analysis showed a significant correlation between CTSD to lipids reproducibly altered level in MASH as shown in Table S8. Among them, the correlations for PE and TG and CTSD, which are well characterized in MASH, are shown in the plots. The dots represent each data point. The dot colors indicate clinical category of the samples. Blue dots represent HCV, green dots represent MASLD and red dots indicate MASH.\u003c/p\u003e","description":"","filename":"supplementaryFigsSMTokuoka250922.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7675910/v1/2faac9d95b8ac028b3e558f8.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Plasma-Targeted Proteomic and Lipidomic Profiling of MASLD, MASH, and Hepatitis C Virus Infection","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eTwo of the most common forms of liver diseases have relatively recently been reclassified: Non-alcoholic fatty liver disease (NAFLD) is now Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), and non-alcoholic steatohepatitis (NASH) is now referred to as Metabolic Dysfunction-Associated Steatohepatitis (MASH)\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. They are characterized by the accumulation of fat and inflammation in the liver, which can often become liver fibrosis, cirrhosis, and even HCC\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Therefore, early diagnosis and appropriate therapeutic interventions are crucial.\u003c/p\u003e\u003cp\u003eMASLD is closely associated with obesity, type 2 diabetes, dyslipidemia, and other lifestyle-related diseases. The global prevalence of such diseases is estimated at around 25%\u003csup\u003e3\u003c/sup\u003e. Recently, lifestyle-related diseases have garnered attention as important clinical and public health challenges. MASH is a progressive form of MASLD, and requires speedier diagnosis, more advanced treatment and management\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Unfortunately, however, non-invasive biomarkers that more precisely diagnose these diseases and better monitor disease progression and treatment efficacy remain scant\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThis study aims to generate reproducible reference data on proteomic and lipidomic alterations in MASLD and MASH, providing hypothesis-generating insights into disease progression and treatment response, and offering a framework to support future biomarker discovery and therapeutic development. To understand the characteristics of MASLD and MASH, individuals infected with HCV and undergoing treatment were used as the comparison group. Hepatitis C Virus (HCV) infection is recognized as a major chronic liver disease. Both MASLD/MASH and HCV are characterized by chronic inflammation, fibrosis, and increased risk of hepatocarcinogenesis. Therefore, HCV represents an informative comparator for delineating the shared and distinct pathogenic pathways of liver inflammation, fibrosis, and metabolic dysregulation. In contrast, collecting a critical mass of plasma samples from healthy individuals proved impractical because healthy people generally have no particular needs to seek medical help. In addition, rigorously excluding subclinical liver abnormalities in such populations is also challenging. For these reasons, healthy controls were not ─ or more precisely, could not be ─ included in this study. Proteomics was selected as an appropriate approach to investigate inflammatory, immune, and fibrotic signaling pathway since only plasma samples were available. Lipidomics was employed to capture the lipid metabolic alterations that are characteristic of chronic liver diseases. Accordingly, proteomic analysis was performed first, followed by lipidomic analysis.\u003c/p\u003e\u003cp\u003eWe have previously worked on integrating multi-omics approaches, including proteomics, lipidomics, and metabolomics\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. However, increased measurement duration and costs, as well as the overwhelming amount of data, has compelled us to employ targeted lipidomics and targeted proteomics in this research. For targeted proteomics, Olink Proteomics' Proximity Extension Assay (PEA)\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e was utilized. Using the Olink Target 96 Series\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e with panels enables quantitative analysis of more than 1,000 proteins in human plasma; however, considering measurement time and costs, we limited our measurements to 184 proteins across 2 panels. Since the progression of MASLD and MASH involves not only fat accumulation but also inflammation and damage to the liver\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e, we selected the inflammation panel from the Olink Target 96 Series.\u003c/p\u003e\u003cp\u003eFurthermore, since MASLD individuals are commonly associated with metabolic syndrome and have an increased risk of cardiovascular disease, Cardiovascular II and III panels were also candidates. We chose the Cardiovascular III panel to explore new mechanistic insights regarding the relationship between liver disease and cardiovascular outcomes\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e all the more because the panel includes fewer well-defined biomarkers. For targeted lipidomics, we analyzed some 500 types of phospholipids and triglycerides (TGs) using the Selected Reaction Monitoring (SRM) method of Liquid Chromatography/Mass Spectrometry (LC/MS)\u003csup\u003e11\u003c/sup\u003e. The methods we employed provide excellent sensitivity for measuring specific proteins and lipid molecules, ensuring quantitativeness. Dual-omics analysis was chosen as the method of research in order to uncover new knowledge regarding disease mechanisms and related therapeutic targets all the more because of the robust synergy provided by the integration of two different types of omics data. This, in turn, enabled us to assess the relationships between liver diseases and proteins or lipids. To the best of our knowledge, this represents the first report of conducting both proteomic and lipidomic analyses at a scale of several hundred plasma samples from Japanese patients diagnosed with chronic liver diseases.\u003c/p\u003e"},{"header":"2. Experimental Section","content":"\u003cp\u003eDemographic Characteristics\u003c/p\u003e\u003cp\u003ePlasma samples from the biobank of the National Center for Global Health and Medicine (197 with MASLD, 81 with MASH and 188 with HCV) and from Saga University Hospital (39 with MASLD and 113 with MASH) were employed in this study. All 618 plasma samples used consisted of three cohorts (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). A liver biopsy was performed to diagnose MASH. Due to the previously-mentioned potential difficulties in accurately diagnosing MASH and MASLD, a certain amount of concern that some of the disease specimens employed in this study might include cases with inaccurate diagnoses remained. Participation was voluntary, and all participants provided signed informed consent forms before registering to participate in this study. All samples from Cohort 1 were used for proteomics. Of Cohort 2 samples, 70 HCV, 77 MASLD, and 39 MASH plasma samples were used for proteomics; and 92 HCV, 81 MASLD, and 30 MASH samples were used for lipidomics. Of the Cohort 3 samples, 72 HCV, 114 MASLD, and 68 MASH plasma samples were used for proteomics; and 96 HCV, 94 MASLD, and 41 MASH were used for lipidomics. Given the limitations in sample volume and the finite availability of research reagents and other resources, performing both proteomics and lipidomics analyses on every sample within Cohort 2 and Cohort 3 was not consistently feasible. Nevertheless, the selection criteria for allocating samples to each analysis were established prior to obtaining the results, and subsequent measurements and analyses were conducted according to these predetermined criteria.\u003c/p\u003e\u003cp\u003eHuman Plasma Samples and Quality Control Sample\u003c/p\u003e\u003cp\u003e This study received approval from the Research Ethics Committee of the Faculty of Medicine of the University of Tokyo (Approval numbers 2019282NI-(2), 2019283NI-(2), and 2019022NI). Ethical approval for this research was obtained from the Ethics Committee of The University of Tokyo Hospital in strict compliance with pertinent university, local, and national guidelines and regulatory standards. To control potential order-dependent systematic errors, the samples from different diagnostic groups were arranged in a dispersed pattern throughout the cohort's measurement sequence. To manage potential long-term drifts in LC-MS sensitivity, a stocked pooled sample consisting of randomly selected 1,000 serum samples was utilized as quality control (QC) samples in the measurement.\u003c/p\u003e\u003cp\u003eReagents\u003c/p\u003e\u003cp\u003eAcetonitrile, 2-propanol (LC/MS grade), and ammonium formate (Wako special grade) from FUJIFILM Wako Pure Chemical Corp. (Osaka, Japan) were the reagents used. Ultrapure water was prepared using the Milli-Q system (Millipore, Billerica, MA, USA). All reagents for PEA proteomics were obtained from Olink Proteomics (Uppsala, Sweden).\u003c/p\u003e\u003cp\u003ePEA Proteomics\u003c/p\u003e\u003cp\u003eCARDIOVASCULAR III and INFLAMMATION panels obtained from Olink Proteomics (Uppsala, Sweden) were used. One \u0026micro;L plasma was used for each panel assay. This experiment utilized the robotic system Maholo equipped with an electronic multi-channel pipette. For the quantification process, the Fluidigm Biomark\u0026trade; HS system or Olink\u0026reg; Signature Q100 system was used for real-time quantitative polymerase chain reaction (qPCR) analysis. Data was processed with the Olink NPX manager software and transformed to Olink\u0026rsquo;s NPX value, a relative protein quantification unit on a log2 scale. NPX values are derived from threshold cycle (Ct) values obtained through qPCR. Each panel was able to measure 92 proteins, and a total of 184 proteins were measured in two panels. This includes three proteins that were included as measurement targets in both panels. Data for 148 proteins detected from among 184 proteins across all 528 plasma samples in this study were used in the analysis.\u003c/p\u003e\u003cp\u003eLipidomics\u003c/p\u003e\u003cp\u003eMeasuring phospholipids and TGs was conducted by lipid extraction from plasma by adding 490\u0026micro;l of 2-propanol onto each 10 \u0026micro;L of plasma sample as described previously with minor modifications\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. The plasma and 2-propanol were mixed with a vortex mixer for 15 seconds at room temperature, and stored at -30\u0026deg;C for one hour. The supernatant after centrifugation at 10,000 \u0026times; g for 10 minutes was collected and transferred to a 384-well plate for measurements.\u003c/p\u003e\u003cp\u003eFor phospholipid measurements, LCMS-8060NX triple quadrupole mass spectrometers equipped with NexeraXS UHPLC (Shimadzu Co., Kyoto, Japan) were used. Shimadzu LabSolutions LCMS software version 5.112 (Shimadzu Co.) was used for instrument operation. Shim-pack Scepter Claris C18-120 columns (2.1 mm \u0026times; 100 mm, 1.9 \u0026micro;m, Shimadzu Co.) were utilized for reversed-phase chromatography. The flow rate was 0.3 mL/min, and the column temperature was 50\u0026deg;C. Mobile phase A consisted of 20 mM NH4HCO2/water, and mobile phase B consisted of 20% acetonitrile and 80% 2-propanol (IPA). The pump gradient was programmed as follows: [time (%A/%B), B Curve setting as 0 unless stated]: from 0 min (70/30) to 0.5 min (70/30), to 14.5 min (10/90) with B Curve setting at -3, 14.6 min (3/97), 18.1 min (3/97), 18.2 min (70/30) and 21 min (70/30). The parameters for the mass spectrometer were set as follows: nitrogen gas used as a nebulizer was set at 2.5 L/min, and as a heating gas set at 10 L/min. The drying gas was set at 10 L/min. Argon gas was used for collision-induced dissociation. Interface temperature was 240\u0026deg;C. Heat block temperature was set at 400\u0026deg;C, and desolvation line temperature was set at 250\u0026deg;C. The injection volume was 3 \u0026micro;L. Table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e shows SRM transitions for phospholipid measurement. The transition list was developed for phospholipid species that can be measured in human blood samples, based on preliminary experiments. These transitions utilize fragmentation for polar head groups in phospholipids or fragmentation for one of the two fatty acyl chains consisting of the lipids. Transitions that utilize fragmentation characteristics for vinyl ether linkage to fatty chains\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e were also used. To consistently represent the phospholipid species analyzed using these SRM, the following nomenclature was used: peaks were identified using SRM with fragmentation of polar head groups, the phospholipid name is represented by the lipid class, followed by the sum of the carbon atoms in the two fatty chains, and the sum of the double bonds in the two fatty chains (e.g., PC_38:6). For peaks identified using SRM with fragmentation of fatty acyl chains, the phospholipid name is represented by the lipid class and the number of carbon atoms and double bonds of the two fatty acyl chains. Following this, the number of carbon atoms and double bonds of the detected fatty acyl chain were specified (e.g., PC_18:2_20:4_FA_18:2 or PC_18:2_20:4_FA_20:4). In addition, for phospholipids containing one ether-linked chain, only the observed single fatty acyl chain is represented, because ether bonds do not typically produce fatty acyl fragments upon fragmentation. When several separated peaks were observed for the same SRM transition, they were named as peak 1, peak 2, and peak 3, in order of increasing retention time.\u003c/p\u003e\u003cp\u003eFor TG measurements, we used to the previously published LC/MS method with minor modifications11 LCMS-8040 triple quadrupole mass spectrometers equipped with Nexera UHPLC (Shimadzu Co.) were used. Shimadzu LabSolutions LCMS software version 5.112 (Shimadzu Co.) was used for instrument operation. Shim-pack Velox C18 (2.1 x 50 mm, 2.7 \u0026micro;m), was utilized for reversed-phase chromatography. The flow rate was 0.4 mL/min, and the column temperature was 45\u0026deg;C. Mobile phase A consisted of 20 mM NH4HCO2/water, and mobile phase B consisted of 100% acetonitrile, and mobile phase C consisted of 100% IPA. The pump gradient was programmed as follows: [time (%A/%B/%C)]: from 0 min (15/15/70) to 0.1 min (15/15/70), to 8.4 min (5/20/75), 9 min (5/20/75), 9.1 min (15/15/70), 11 min (15/15/70). The parameters for the mass spectrometer were set as follows: nitrogen gas used as a nebulizer was set at 2.5 L/min, and drying gas was set at 10 L/min. Argon gas was used for collision-induced dissociation. Heat block temperature was set at 400\u0026deg;C, and desolvation line temperature was set at 250\u0026deg;C. The injection volume was 4 \u0026micro;L. The list for SRM transitions for TGs is shown in Table S3. The transition list was developed for TG species that can be measured in human blood samples, based on preliminary experiments and the SRM transitions detected from all samples were used as result data. In the SRM transitions, Q1 was set as the parent ion of the ammonium adduct, and Q3 was set as the neutral loss of a fatty chain. The species-level TG name is expressed as the sum of carbon atoms and the sum of double bond equivalents of the three fatty chains. For the TG peaks observed in our SRM analysis, we named them by appending the number of carbon atoms and the number of double bonds of the fatty acyl chain detected as the neutral loss. Peak areas for each SRM were calculated by Traces software\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. The QC measurements were performed every 12 samples, and raw peak areas were normalized using the systematic error removal by random forest (SERRF) method with the QC measurements\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Each normalized SRM peak value was summed for each lipid class, and the individual peak values were then expressed as a ratios to the summed lipid class values.\u003c/p\u003e\u003cp\u003eStatistics\u003c/p\u003e\u003cp\u003eOne-way ANOVA and Student's t-test (where p-values were adjusted for false discovery rate (FDR) using the Benjamini-Hochberg procedure), and Pearson's correlation analysis were performed using MetaboAnalyst 6.0 software.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Box plots, volcano plots, and scatter plots were constructed using R software (version 4.4.2).\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003eTargeted proteomics\u003c/p\u003e\n\u003cp\u003eTargeted proteomics was conducted on plasma samples from 88 individuals (35 with MASLD and 53 with MASH) in Cohort 1, and eight proteins showed significant differences (FDR-adjusted p-values are less than 0.05) between MASLD and MASH (Table 1-1).\u003c/p\u003e\n\u003cp\u003eTo confirm reproducibility across different samples, targeted proteomics was conducted on plasma samples from 186 individuals (70 with MASLD, 77 with MASH, and 39 with HCV) in Cohort 2, revealing significant differences (FDR-adjusted p-values are less than 0.05) in 88 proteins (Table 1-2).\u003c/p\u003e\n\u003cp\u003eAmong these, 47 proteins marked with an asterisk (\u003csup\u003e*\u003c/sup\u003e) in Table 1-2 exhibited significant differences (FDR-adjusted p-values are less than 0.05) between MASLD and MASH, with seven proteins marked with (\u003csup\u003e#\u003c/sup\u003e) in Table 1-2 being reproduced in both Cohort 1 and Cohort 2. The seven proteins that were reproducible are as follows: CASP-8 (caspase-8), CCL20 (C-C motif chemokine ligand 20), CTSD (cathepsin D), MMP-3 (matrix metalloproteinase-3), SCF (stem cell factor), TRAIL (Tumor Necrosis Factor -related apoptosis-inducing ligand), and TWEAK (Tumor Necrosis Factor-related weak inducer of apoptosis).\u003c/p\u003e\n\u003cp\u003eTo confirm reproducibility using plasma samples collected from the same 186 individuals as Cohort 2 at different times, we conducted targeted proteomics on 254 plasma samples in Cohort 3 (some individuals had blood drawn twice on different days) (Table 1-3). The results indicated significant variations in 66 proteins (Table 1-3), with 28 proteins marked with an asterisk (\u003csup\u003e*\u003c/sup\u003e) in Table 1-3 showing significant differences (FDR-adjusted p-values are less than 0.05) between MASLD and MASH. Among these 28 proteins, seven proteins marked with (\u003csup\u003e#\u003c/sup\u003e) in Table 1-3 were reproduced across all three cohorts (Figures 1a-g).\u003c/p\u003e\n\u003cp\u003eCASP-8, CCL20, and CTSD were elevated in MASH. MMP-3, SCF, TRAIL, and TWEAK were decreased in MASH. Comparing HCV and the other groups, the levels of CASP-8, MMP-3, TRAIL and TWEAK differed significantly from those in MASH in both Cohort 2 and Cohort 3 (Table 1-2 and Table 1-3). Correlation analysis of these seven proteins within all three cohorts revealed that the following pairs showed significant correlations with p \u0026lt; 0.01 across all three cohorts: CTSD/CCL20, MMP-3/SCF, MMP-3/TRAIL, MMP-3/TWEAK, SCF/TRAIL, SCF/TWEAK, and TWEAK/TRAIL. The correlation between CASP-8 and CCL20 was somewhat significant only in Cohort 1 at p = 0.016, whereas it was significant in Cohort 2 and Cohort 3 (p \u0026lt; 0.01) (Table S4, Figure S1). All correlations were positive.\u003c/p\u003e\n\u003cp\u003eTable 1-1. Proteins with differential levels among clinical categories in MASH and MASLD in Cohort 1.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eProtein\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eUniprot ID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFDR-adjusted p-value (BH)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSCF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eP21583\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.0276\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.00036\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTWEAK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eO43508\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.0276\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.00037\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCCL20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eQ9NRJ3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.0324\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.00088\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003et-PA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eP00750\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.0324\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.00094\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMMP-3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eP08254\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.0324\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.00120\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTRAIL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eP50591\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.0324\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.00136\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCASP-8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eQ14790\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.0324\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.00153\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCTSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eP07339\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.0419\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.00227\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eFDR-adjusted p-values were adjusted under the Benjamini-Hochberg (BH) procedure.\u003c/p\u003e\n\u003cp\u003eTable 1-2. Proteins with differential levels among clinical categories in Cohort 2.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eProtein\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eUniprot ID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eFDR-adjusted p-value (BH)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003eTukey\u0026apos;s HSD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eCASP-8\u003csup\u003e*#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ14790\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e3.32E-16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eSELE\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP16581\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.32E-11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eLDL receptor\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP01130\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e2.29E-09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eIGFBP-2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP18065\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e5.20E-09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eFGF-21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ9NSA1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e4.74E-08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eMCP-3\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP80098\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e4.74E-08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eLAP TGF-beta-1\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP01137\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e3.19E-07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eSELP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP16109\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e4.50E-07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eHGF\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP14210\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e4.60E-07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003ePAI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP05121\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e4.60E-07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eFABP4\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP15090\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.42E-06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eCCL16\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eO15467\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e4.36E-06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eITGB2\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP05107\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e4.36E-06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eCASP-3\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP42574\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e5.90E-06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eIL-1RT2\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP27930\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e9.88E-06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eGP6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ9HCN6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.40E-05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eTNFSF14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eO43557\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.40E-05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eIL-12B\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP29460\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.70E-05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eCXCL10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP02778\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.87E-05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eGDF-15\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ99988\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e2.96E-05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eIL7\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP13232\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e3.10E-05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eCDCP1\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ9H5V8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e9.02E-05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eOSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP13725\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e9.02E-05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003ePDGF subunit A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP04085\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e9.22E-05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003et-PA\u003csup\u003e*#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP00750\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.04E-04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eCXCL9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ07325\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.41E-04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eEN-RAGE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP80511\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.55E-04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003ePCSK9\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ8NBP7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.58E-04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eCCL20\u003csup\u003e*#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP78556\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.63E-04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eCHI3L1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP36222\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.00016305\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eRARRES2\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ99969\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.63E-04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eTWEAK\u003csup\u003e*#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eO43508\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.00019955\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eIL10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP22301\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.00039744\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eIGFBP-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP08833\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.00042593\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eIL-18BP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eO95998\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.00042593\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eSTAMBP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eO95630\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.00051626\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eJAM-A\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ9Y624\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0005893\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eCTSD\u003csup\u003e*#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP07339\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.00069465\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eTRANCE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eO14788\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.00090228\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eTNFRSF9\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ07011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0011404\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eCD163\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ86VB7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0011675\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eSCF\u003csup\u003e*#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP21583\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0011675\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eTIMP4\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ99727\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0011675\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eCCL19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ99731\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0012062\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eCXCL5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP42830\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0012062\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eTRAIL\u003csup\u003e*#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP50591\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0015401\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eIGFBP-7\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ16270\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0015982\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eADA\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP00813\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.001641\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eIL2-RA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP01589\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0017794\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003evWF\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP04275\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0020453\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eAP-N\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP15144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.002273\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eTNFRSF14\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ92956\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0023743\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eOPG\u003csup\u003e_c\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eO00300\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0028465\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eSLAMF1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ13291\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0028689\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eAZU1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP20160\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0035057\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eGal-4\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP56470\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0041724\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eMMP-9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP14780\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0046299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eIL-18R1\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ13478\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0052014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eOPG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eO00300\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0057416\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eTLT-2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ5T2D2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0057416\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eMMP-3\u003csup\u003e*#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP08254\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0073831\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eTNFRSF10C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eO14798\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0073831\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eCD40\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP25942\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0078302\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eTGF-alpha\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP01135\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.0080214\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eCPA1\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP15085\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.008054\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eCTSZ\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ9UBR2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.010977\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eFAS\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP25445\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.011105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eCXCL11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eO14625\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.011938\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003ePON3\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ15166\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.011938\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eTNFB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP01374\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.011938\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eALCAM\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ13740\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.013208\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eCCL11\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP51671\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.013208\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eLTBR\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP36941\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.013626\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eMPO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP05164\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.016457\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eCOL1A1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP02452\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.019287\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eEGFR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP00533\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.019287\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eCD244\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ9BZW8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.020751\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eIL-1RT1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP14778\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.025788\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003ePD-L1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ9NZQ7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.026069\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eTNF-R1\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP19438\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.026383\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eNotch 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ9UM47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.026546\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eCD5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP06127\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.027523\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eCD6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP30203\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.027523\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eCSTB\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP04080\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.028853\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003euPA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP00749\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.032758\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eAXL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP30530\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.039458\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003ePLC\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eP98160\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.04295\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eTFF3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eQ07654\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.045234\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 293px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eProteins with FDR-adjusted p-values of less than 0.05 for the one-way ANOVA test were listed. * indicates significant differences between MASLD and MASH within Cohort 2. # indicates that the significant difference observed in Cohort 1 was reproduced in Cohort 2. OPG1 was measured using both panels. Data from the CARDIOVASCULAR III panel for these proteins are indicated by a superscript \u0026quot;_c\u0026quot;.\u003c/p\u003e\n\u003cp\u003eTable 1-3. Proteins with differential levels among clinical categories in Cohort 3.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eProtein\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eUniprot ID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eFDR-adjusted p-value (BH)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eTukey\u0026apos;s HSD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eCASP-8\u003csup\u003e*#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eQ14790\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e4.97E-09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eSELE\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP16581\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e4.59E-07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eIGFBP-2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP18065\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e4.69E-07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eTNFSF14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eO43557\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e4.69E-07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eIGFBP-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP08833\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e1.39E-06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eIL7\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP13232\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e1.58E-06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eLDL receptor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP01130\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e1.63E-06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eFGF-21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eQ9NSA1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e1.75E-06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eOSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP13725\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e1.75E-06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eCASP-3\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP42574\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e2.25E-06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eTWEAK\u003csup\u003e*#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eO43508\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e7.04E-06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eLAP TGF-beta-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP01137\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e7.43E-06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eSELP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP16109\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e2.33E-05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eCTSD\u003csup\u003e*#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP07339\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e2.34E-05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003ePAI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP05121\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e6.60E-05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eCXCL5\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP42830\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e6.90E-05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eCXCL9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eQ07325\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.0000768\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eMMP-3\u003csup\u003e*#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP08254\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.0000768\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003ePDGF subunit A\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP04085\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e7.68E-05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003ePON3\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eQ15166\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e7.68E-05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eSCF\u003csup\u003e*#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP21583\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e7.68E-05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eCHI3L1\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP36222\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.00011115\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eGP6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eQ9HCN6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.00013729\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eMCP-3\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP80098\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.00014742\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eMMP-9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP14780\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.00017729\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eSTAMBP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eO95630\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.00021226\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eFABP4\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP15090\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.00030143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eTRAIL\u003csup\u003e*#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP50591\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.00035458\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eOPG\u003csup\u003e_\u003c/sup\u003e\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eO00300\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.00037758\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eGDF-15\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eQ99988\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.00038836\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eMPO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP05164\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.00060826\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eCCL16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eO15467\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.00094184\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eTFF3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eQ07654\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.0011618\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eTGF-alpha\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP01135\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.0011618\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eIL-1RT2\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP27930\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.0014993\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eAZU1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP20160\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.0021148\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eTRANCE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eO14788\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.0023726\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eTLT-2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eQ5T2D2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.002569\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eCCL23\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP55773\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.0026187\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eEN-RAGE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP80511\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.0038445\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eOPG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eO00300\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.004438\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eIL8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP10145\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.0054583\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eCCL20\u003csup\u003e*#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP78556\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.0060553\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eSCGB3A2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eQ96PL1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.0064909\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eCDCP1\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eQ9H5V8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.0070516\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eCCL11\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP51671\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.0073257\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eDNER\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eQ8NFT8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.013792\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eNotch 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eQ9UM47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.013792\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eIL-18BP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eO95998\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.015443\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eTIMP4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eQ99727\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.015443\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eCPA1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP15085\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.015791\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eTFPI\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP10646\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.017396\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eHGF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP14210\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.01765\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eITGB2\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP05107\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.01987\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eIFN-gamma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP01579\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.024925\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eCD93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eQ9NPY3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.028568\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eMCP-2\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP80075\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.028568\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eIL2-RA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP01589\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.028606\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eJAM-A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eQ9Y624\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.029976\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eCCL28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eQ9NRJ3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.03836\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eFGF-19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eO95750\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.039581\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eIL6\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP05231\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.039581\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eEGFR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP00533\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.042159\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eGal-4\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP56470\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.043253\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eIGFBP-7\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eQ16270\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.043253\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003euPA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eP00749\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e0.047227\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eProteins with FDR-adjusted p-values of less than 0.05 for the one-way ANOVA test were listed. * indicates significant differences between MASLD and MASH within Cohort 3. # ndicates significant differences between MASLD and MASH, reproduced across all three cohorts (Figures 2a-2g). OPG1 was measured using both panels. Data from the CARDIOVASCULAR III panel for these proteins are indicated by a superscript \u0026quot;_c\u0026quot;.\u003c/p\u003e\n\u003cp\u003eTargeted Lipidomics\u003c/p\u003e\n\u003cp\u003eIn Cohort 2 and Cohort 3, targeted phospholipids analysis was performed and revealed significant differences in 131 phospholipid species in Cohort 2 (Table S5-1) and in 129 phospholipid species in Cohort 3 (Table S5-2), 47 of which showed significant differences between MASLD and MASH in Cohort 2 (Table S5-1) and 49 in Cohort 3 (Table S5-2). Among these, 29 phospholipids demonstrated reproducibility (Table 2). Of these 29, 12 species were identified as diradyl (with two fatty chains) PE, including seven species with an ether bond of which five were presumed to have a vinyl-ether bond. Examining the 12 PEs that showed significant alterations in either Cohort 2 or Cohort 3, all seven ether PEs were significantly decreased in MASH compared to MASLD. PEs with two ester bonds, on the other hand, were significantly increased in MASH compared to those in MASLD in both Cohort 2 and Cohort 3 (Figure 2).\u003c/p\u003e\n\u003cp\u003eTable 2. Phospholipids with differential levels reproduced in Cohort 2 and Cohort 3 between MASLD and MASH.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003eLipid Name\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003eLipid Class\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eFDR-adjusted p-value (BH) Cohort 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eFDR-adjusted p-value (BH) Cohort 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eTukey\u0026apos;s HSD Cohort 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003eTukey\u0026apos;s HSD Cohort 3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003eLPC_18:2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.88E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2.07E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003eLPC_18:2_FA_18:2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.22E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.12E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003eLPC_24:0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.08E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.60E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003ePC_18:2_20:4_FA_18:2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.24E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.37E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003ePC_33:1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.89E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.16E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003ePC_36:1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.08E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2.57E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003ePC_O-34:2_FA_18:2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e4.41E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.16E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003ePC_O-34:2_peak1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.08E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e5.47E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003ePC_O-34:3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2.25E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e4.20E-04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003ePC_O-36:2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.14E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.84E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003ePC_O-36:2_FA_18:2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.15E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e5.28E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003ePC_O-36:3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e7.44E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.35E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003ePC_O-38:5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2.33E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2.97E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003eLPE_20:4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e4.74E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e9.62E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003ePE_16:0_22:6_FA_16:0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2.23E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.84E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003ePE_18:0_22:6_FA_18:0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e9.66E-04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e4.94E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003ePE_34:1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.22E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e6.87E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003ePE_38:6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2.23E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e9.91E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003ePE_40:6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.09E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.09E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003ePE_O-38:5_FA_22:5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2.34E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e4.18E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003ePE_O-40:6_FA_22:5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e4.66E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.16E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003ePE_O-38:6_FA_22:5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e9.55E-04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2.57E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003ePE_P-16:0_22:5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e4.78E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2.57E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003ePE_P-18:0_22:5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.46E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.16E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003ePE_P-18:1_22:4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2.42E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.16E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003ePE_P-18:1_22:5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003ePE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.24E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.18E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003eSM_36:0;O2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003eSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e9.55E-04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.36E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003eSM_38:0;O2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003eSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.46E-04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e8.20E-04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003ePhospholipids with an FDR-adjusted p-value of less than 0.05 for the one-way ANOVA test and showed significant change with Tukey\u0026rsquo;s HSD post hoc test between MASH and MASLD were listed.\u003c/p\u003e\n\u003cp\u003eAll detected PE species are displayed in a volcano plot, and most components with ether bonds were observed to exhibit low values in the MASH (Figure 2e). Among the 17 phospholipids other than PE, 10 were diradyl phosphatidylcholine (PC), four were lyso PC or lyso PE, and three were saturated sphingomyelin (SM). Similar to PE, ether-linked PC was also found to be lower in MASH (Figure 2f). The trend of lower and higher levels in ether and diacyl lipids in MASH, however, appears to be more pronounced in PE than in PC. The ether-linked phospholipids for which reproducible changes were observed contained two or more unsaturated bonds. Regarding SMs, three SMs with saturated fatty acids were increased in MASH compared to MASLD (Figure 2c). The four lyso PLs were all lower in MASH (Figure 2d). For HCV, 85 phospholipid molecules showed significant differences in both Cohort 2 and Cohort 3 (Observed differences between HCV and MASLD or MASH in both cohorts are indicated by a \u0026ldquo;\u0026dagger;\u0026rdquo; in Table S5-1 and Table S5-2). Among these, 17 phospholipid molecules exhibited significant difference in both Cohort 2 and Cohort 3 between HCV and MASLD and also between HCV and MASH (Table 3), though no changes were observed for MASLD and MASH (excluding one SM that changed significantly in only one cohort). They included eight SM and six PC components; since\u003c/p\u003e\n\u003cp\u003eTable 3. Phospholipids with differential levels in HCV reproduced in Cohort 2 and Cohort 3.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eLipid Name\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003eLipid Class\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eFDR-adjusted p-value (BH) Cohort 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eFDR-adjusted p-value (BH) Cohort 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eTukey\u0026apos;s HSD Cohort 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003eTukey\u0026apos;s HSD Cohort 3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eLPC_22:6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.24E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.18E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003ePC_38:3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2.25E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.47E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003ePC_O-32:1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.70E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.55E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003ePC_O-34:1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2.17E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e9.48E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003ePC_O-34:2_FA_18:1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.46E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.16E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003ePC_O-34:2_peak2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.46E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2.34E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003ePC_O-36:2_FA_18:1_peak1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.79E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.16E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003ePI_18:0_18:2_FA_18:2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003ePI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2.03E-05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e8.20E-04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003ePI_36:2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003ePI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e7.92E-05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e6.87E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eSM_34:0;O2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003eSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e6.80E-04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e6.55E-04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eSM_35:2;O2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003eSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2.48E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.83E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eSM_36:1;O2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003eSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.50E-06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.39E-07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eSM_36:2;O2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003eSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.13E-06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.39E-07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eSM_38:1;O2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003eSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.91E-08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e9.26E-08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eSM_40:1;O2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003eSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3.77E-07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2.34E-04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eSM_40:2;O2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003eSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.53E-09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.39E-07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eSM_40:3;O2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003eSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.54E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e5.40E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-1_HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003ePhospholipids with an FDR-adjusted p-value of less than 0.05 for the one-way ANOVA test and showed siginificant change with Tukey\u0026apos;s HSD post hoc test between HCV and MASLD or HCV and MASH.\u003c/p\u003e\n\u003cp\u003eSM has fewer components as targets in this lipidomics research than PC due to the lower variety of SM species in plasma, we conclude that a larger proportion of SMs accounted for the altered lipids in HCV compared to MASH and MASLD (35 targeted features for SMs and 204 targeted features for PCs).\u003c/p\u003e\n\u003cp\u003eNext, targeted TG analysis was conducted. In Cohort 2, 26 TG species had an FDR-adjusted p-value smaller than 0.1 (raw p value \u0026lt; 0.02) by ANOVA (Table S6-1), among which 18 TGs marked with an asterisk (\u003csup\u003e*\u003c/sup\u003e) in Table S6-1 exhibited significant differences between MASLD and MASH. To confirm reproducibility, TG analysis was performed in Cohort 3, and differences in 27 TG species (Table S6-2) were identified. Results showed 14 species indicated with an asterisk (\u003csup\u003e*\u003c/sup\u003e) in Table S6-2 with differences between MASLD and MASH. Eight TG species marked with (\u003csup\u003e#\u003c/sup\u003e) in Table S6-1 and Table S6-2 showed proof and reproducible differences between MASLD and MASH across both Cohort 2 and Cohort 3 (Table 4, Fig 3). Of those eight TG molecular species, five contained 18:2 fatty chains. Of note, all five of the 18:2-containing TG components were lower abundance in MASH than in MASLD. The patterns of low level of 18:2 fatty acyl chain containing TG in MASH were confirmed by a volcano plot of both Cohort 2 and Cohort 3 (Fig S3). To detect characteristics of HCV against MASH or MAFLD, we also listed TG components that were different by ANOVA but not between MASH and MASLD (Table S7, Figure S4).\u003c/p\u003e\n\u003cp\u003eCorrelations for protein-to-lipid interaction between the proteins that showed significant variation across the three cohorts and the lipids that exhibited changes in Cohort 2 and Cohort 3 (Table S8) were analyzed. Of the seven proteins (CASP-8, CCL20, CTSD, MMP-3, SCF, TRAIL, and TWEAK) that showed good reproducible changes between MASLD and MASH, CTSD in particular correlated with several PEs: positively with two diacyl PEs and negatively with six ether PEs (Fig S5). In addition, CTSD showed a negative correlation with five TGs containing FA18:2 (Fig S5). Thus, CTSD predominantly correlated with lipids that characterized MASH with lipidomic results. CCL20 also showed a similar trend (one diacyl PE, three ether PEs, two TGs containing FA18:2) although it did not correlate with as many lipids as CTSD. MMP3 was characterized by a negative correlation with PE with FA22:6. For SCF, a negative correlation with lipids having mono-unsaturation was characteristic. Three mono-saturated phospholipids and one TG with mono-saturated fatty acids all showed a negative correlation with SCF (Table S8).\u003c/p\u003e\n\u003cp\u003eTable 4. Triglycerides reproduced in Cohort 2 and Cohort 3 with differential levels between MASLD and MASH.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"638\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003eLipid Name\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003ep-value\u003cbr\u003e\u0026nbsp;Cohort 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003ep-value\u003cbr\u003e\u0026nbsp;Cohort 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eFDR-adjusted p-value (BH) Cohort 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003eFDR-adjusted p-value (BH) Cohort 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eTukey\u0026apos;s HSD\u003cbr\u003e\u0026nbsp;Cohort 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eTukey\u0026apos;s HSD\u003cbr\u003e\u0026nbsp;Cohort 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eTG Name Species level\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003eContaining fatty chain\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003eTG_50:2-FA_18:1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1.53E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2.04E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.0990\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.0999\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eTG_50:2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003eFA_18:1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003eTG_52:3-FA_16:0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e7.41E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e6.87E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.0956\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.0612\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e2_MASLD-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eTG_52:3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003eFA_16:0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003eTG_52:3-FA_18:2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1.22E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e3.63E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.0990\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.0612\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eTG_52:3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003eFA_18:2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003eTG_52:4-FA_16:0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e7.18E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1.41E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.0956\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.0373\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eTG_52:4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003eFA_16:0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003eTG_52:4-FA_18:2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e9.05E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1.30E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.0956\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.0373\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eTG_52:4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003eFA_18:2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003eTG_52:5-FA_18:2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e7.54E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e3.48E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.0956\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.0612\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eTG_52:5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003eFA_18:2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003eTG_54:5-FA_18:2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e4.69E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1.38E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.0956\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.0373\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eTG_54:5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003eFA_18:2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003eTG_54:6-FA_18:2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1.01E-02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1.29E-03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.0956\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e0.0373\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3_MASH-1_HCV; 3_MASH-2_MASLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eTG_54:6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003eFA_18:2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTriglyderides with FDR-adjusted p-values of less than 0.05 for the one-way ANOVA test and which showed siginificant change with Tukey`s HSD post hoc test between MASH and MASLD or HCV and MASH in both Cohort 2 and Cohort 3 were listed.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe relationship between each protein and lipid molecule for the results obtained in this study is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e4\u003c/span\u003e (related molecules are connected to each other by lines). CASP-8 is a crucial enzyme to initiating apoptosis via the extrinsic pathway mediated by DR4 and DR5 that serves as the starting point. In MASH, hepatocyte apoptosis increases, and CASP-8 activation contributes to the progression of liver inflammation and fibrosis\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Similarly, in HCV infection, cellular stress associated with viral replication activates CASP-8, inducing hepatocyte apoptosis. HCV-mediated apoptosis by CASP-8 also contributes to chronic inflammation by releasing apoptotic debris. However, some reports suggest that HCV modulates CASP-8 activity to delay apoptosis and prefer viral persistence, however, this mechanism remains unclear\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe chemokine CCL20 recruits CCR6-expressing immune cells, and becomes elevated in MASH liver tissue. This, in turn, intensifies inflammatory responses and immune cell infiltration\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. In HCV infection, antigen presentation activates immune cells and upregulates CCL20, further aggravating inflammation. The correlation between CASP-8 and CCL20 expression suggests that apoptotic signals induce CCL20 secretion, exacerbating inflammation even further. Persistent CCL20 elevation in chronic HCV infection likely contributes to excessive immune infiltration and fibrosis, though its mechanistic role is still under investigation\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe lysosomal enzyme CTSD is involved in protein degradation and autophagy, and increases as MASLD progresses to MASH, a sign of enhanced cellular stress responses\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. The significant correlation between CCL20 and CTSD expression implies that macrophage activation and lysosomal function modulation associated with inflammation are involved. In HCV infection, viral replication alters lysosomal function, potentially modulating CTSD expression and supporting viral persistence, all of which must be investigated further. The MMP-3 enzyme is involved in extracellular matrix (ECM) remodeling and decreased in MASH, potentially promoting ECM accumulation and fibrosis\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. MMP-3 also affects lipid metabolism through adipocyte remodeling and inflammation regulation\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. The observed reductions in MMP-3, SCF, TRAIL, and TWEAK suggest the presence of damaged liver repair and immune clearance mechanisms that encourage fibrosis progression.\u003c/p\u003e\u003cp\u003eThe growth factor SCF regulates hematopoietic and hepatic stem cells\u003csup\u003e\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e, and typically increases with early injury or stress, as in MASLD cases where SCF-producing cells decline. As a result, regenerative capacity is diminished. Reduced SCF in a fibrotic, inflammatory environment can prevent liver repair.\u003c/p\u003e\u003cp\u003eThe TRAIL protein induces apoptosis by binding to DR4 and DR5 receptors\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e, was decreased in MASH, indicating reduced immune clearance of hepatocytes. In HCV infection, TRAIL expression is variable but can influence hepatocyte injury and clearance\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eTWEAK protein regulates cell survival, differentiation, and apoptosis via the Fn14 receptor\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. These levels were elevated in MASH, signifying involvement in hepatocyte injury and fibrosis progression. Both TRAIL and TWEAK are members of the tumor necrosis factor (TNF) superfamily involved in apoptosis regulation\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Their concurrent downregulation in MASH suggests a reduction in immune cell-mediated hepatocyte clearance, all of which contribute to chronic inflammation. The significant correlation between TRAIL and TWEAK expression implies a coordinated regulatory mechanism in hepatic immune responses.\u003c/p\u003e\u003cp\u003eIn MASH, ether-linked PE (PE O (1-O-alkyl-2-acyl-sn-glycero-3-phosphoethanolamine), PE P (1-O-(1'Z-alkenyl)-2-acyl-sn-glycero-3-phosphoethanolamine, plasmalogen) is reduced, whereas ester-linked PE is increased. These shifts driven by oxidative stress and peroxisomal dysfunction\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e, \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003emay\u003c/span\u003e increase membrane vulnerability to lipid peroxidation\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e, promote apoptosis, and destabilize membrane homeostasis\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eSphingomyelins (SM) containing saturated fatty acids that rigidify lipid rafts\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. SMs increased in MASH, which contribute a strong resistance to insulin.\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. Conversely, unsaturated SM (SM_38:2, SM_40:2) is elevated in MASLD, indicating lipid metabolism alterations.\u003c/p\u003e\u003cp\u003eOn the one hand, the number of TG species containing linoleic acid (18:2) diminished in MASH, likely because of increased β-oxidation or prevented VLDL incorporation. TGs containing DHA or AA, on the other hand, were maintained, likely reflecting their essential structural roles.\u003c/p\u003e\u003cp\u003eThe CTSD protein showed a positive correlation with TGs containing linoleic acid, suggesting a role in lipid turnover\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. In advanced stages of a chronic disease, lysosomal dysfunction may reduce lipid degradation\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e, which alters TG homeostasis. SCF correlated inversely with monounsaturated fatty acid (MUFA)-containing lipids across Cohort 2 and Cohort 3, consistent with compensatory increases in anti-inflammatory MUFAs\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e, that attenuate SCF/c-Kit signaling by modifying membrane lipid raft composition\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. This suggests a lipid-mediated feedback mechanism modulating SCF activity during chronic injury.\u003c/p\u003e\u003cp\u003eAlthough correlations between CCL20 and lipid species were less consistent, inverse associations with ether-type PE and TGs containing linoleic acid were observed in both Cohorts 2 and Cohort 3, suggesting interaction occurs. No reproducible lipid correlations were identified for CASP-8, TRAIL, or TWEAK.\u003c/p\u003e\u003cp\u003eFurthermore, this large-scale dual-omics analysis performed exclusively on Japanese patients provides population-specific insights that complement existing data from non-Japanese cohorts, and highlight the need for diverse datasets to advance biomarker discovery and precision medicine in chronic liver diseases.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eOur study highlights molecular features associated with MASH and HCV infection, especially in apoptosis, immune response, and lipid metabolism. CASP-8 activation, together with CCL20, points to apoptotic signals that likely drive immune cell recruitment and chronic inflammation. Lipid alterations in MASH, the reduction of ether-linked PE, and the increase in ester-linked PE and saturated SM all suggest a shift in membrane composition affecting insulin signaling and oxidative stress resistance. The accumulation of linoleic acid-containing TGs seems to exacerbate inflammation and fibrosis by promoting eicosanoid production.\u003c/p\u003e\n\u003cp\u003eThe inverse correlation between CCL20 and ether-linked PE or linoleic acid-containing TGs indicates a potential interaction between immune signaling and lipid metabolism. SCF regulates hematopoietic and hepatic stem cells, and shows a negative relationship with MUFA containing lipids. This is likely related to feedback regulation within an injured liver. CTSD, a lysosomal enzyme involved in protein and lipid degradation, inversely correlates with linoleic acid-containing TGs, revealing a potential role in lipid turnover important for regulating body weight and metabolic health. The roles of CASP-8, TRAIL, and TWEAK in apoptosis and fibrosis are known, and showed no reproducible correlations with lipid species. This suggests that their primary functions in MASH and HCV pathogenesis are likely independent of lipid alterations.\u003c/p\u003e\n\u003cp\u003eThese findings should be regarded as hypothesis-generating and reference-quality, offering reproducible proteomic and lipidomic data from several hundred Japanese patients. Rather than establishing definitive diagnostic biomarkers or mechanisms, this framework provides a valuable resource to guide future studies in risk stratification, therapeutic monitoring, and mechanistic validation across broader populations.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCASP-8, caspase-8; CCL20, C-C motif chemokine ligand 20; CTSD, cathepsin D; ECM, extracellular matrix; FA, fatty acid; FDR, false discovery rate; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LC/MS, liquid chromatography/mass spectrometry, MASH, metabolic dysfunction-associated steatohepatitis; MASLD, metabolic dysfunction-associated steatotic liver disease; MMP-3, matrix metalloproteinase-3; MUFA, monounsaturated fatty acid; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PEA, proximity extension assay; PL, phospholipid; QC, quality control; qPCR, quantitative polymerase chain reaction; SCF, stem cell factor; SM, sphingomyelin; SRM, selected reaction monitoring; TG, triglyceride; TNF, tumor necrosis factor; TRAIL, tumor necrosis factor -related apoptosis-inducing ligand; TWEAK, tumor necrosis factor-related weak inducer of apoptosis; VLDL, very low-density lipoproteins.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eACKNOWLEDGMENTS\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to express our gratitude to the study participants and all the investigators involved in the study. We are deeply grateful to Dr. Tohru Natsume and members of Robotic Biology Institute Inc. (RBI) for providing us with a humanoid robot Maholo to improve accurate sample handlings. We thank Yoshihiro Kita and Hatsue Igarashi for their assistance. We would like to express our appreciation to Masaki Yamada for his contribution to the creation of our lipidomics methods.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eY.O. conceived and supervised the project and wrote the manuscript. S.M.T. was responsible for lipidomics analyses and preparation of figures and tables. F.H. and A.K. conducted the proteomics experiments. M.S., H.T., and M.M. were in charge of the collection and storage management of clinical specimens.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was supported by AMED (23tm0624002j0001), AMED (243fa627011h003) and AMED (24ae0121041s0104) (to Y.O.) and JSPS KAKENHI (21K06853) (to S.M.T.). The Department of Lipidomics is supported by the Shimadzu Corporation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe mass spectrometry data have been deposited to Zenodo (Accession Number: 10.5281/zenodo.15736637).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study received approval from the Research Ethics Committee of the Faculty of Medicine of the University of Tokyo (Approval numbers 2019282NI-(2), 2019283NI-(2), and 2019022NI).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\u003cp\u003eCorresponding Author\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e*\u003c/sup\u003e Yoshiya Oda, The University of Tokyo, Graduate School of Medicine\u003c/p\u003e\n\u003cp\u003e7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0051 Japan, Phone: +81-3-5841-3540, e-mail: [email protected]\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDale K, Fallouh Y, Alkhouri N. 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Int J Mol Sci. 2021;22(1):330. doi:10.3390/ijms22010330.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"clinical-proteomics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"clip","sideBox":"Learn more about [Clinical Proteomics](http://clinicalproteomicsjournal.biomedcentral.com/)","snPcode":"12014","submissionUrl":"https://submission.nature.com/new-submission/12014/3","title":"Clinical Proteomics","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"proteomics, lipidomics, multi-omics, MASH, MASLD, HCV, plasma, clinical samples","lastPublishedDoi":"10.21203/rs.3.rs-7675910/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7675910/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eMetabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are chronic liver diseases characterized by lipid accumulation and persistent inflammation, often progressing to fibrosis or hepatocellular carcinoma (HCC). Hepatitis C virus (HCV) infection shares overlapping pathological features, including chronic inflammation and fibrogenesis. Despite their prevalence, reproducible molecular markers to distinguish disease stages or inform treatment monitoring remain limited.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe conducted targeted proteomic and lipidomic profiling of several hundred plasma samples from Japanese patients diagnosed with MASLD, MASH, or HCV infection. Targeted proteomics quantified 184 plasma proteins using the Olink Proximity Extension Assay, and targeted lipidomics quantified approximately 500 phospholipid and triglyceride species using LC-MS-based selected reaction monitoring. Reproducibility was assessed across three independent cohorts.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eSeven proteins consistently exhibited differential abundance: CASP-8, CCL20, and CTSD were elevated in MASH, while SCF, MMP-3, TRAIL, and TWEAK were downregulated. Similar alterations were observed in HCV, indicating shared immune dysregulation. Lipidomic analysis revealed decreased ether-linked phosphatidylethanolamine (PE), increased ester-linked PE, and elevated saturated sphingomyelin in MASH, reflecting oxidative stress and impaired lipid metabolism. Triglycerides containing linoleic acid (18:2) were consistently reduced in MASH and correlated with CTSD, implicating lysosomal pathways. Correlation analyses indicated coordinated relationships between protein and lipid alterations, suggesting immune\u0026ndash;lipid cross-talk during disease progression.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eThis study provides the first large-scale dual-omics plasma analysis in Japanese cohorts with MASLD, MASH, and HCV. Rather than establishing definitive diagnostic biomarkers, our results should be interpreted as reproducible, hypothesis-generating reference data. These findings provide a framework and resource for future studies aiming at risk stratification, therapeutic monitoring, and mechanistic validation in chronic liver disease.\u003c/p\u003e","manuscriptTitle":"Plasma-Targeted Proteomic and Lipidomic Profiling of MASLD, MASH, and Hepatitis C Virus Infection","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-10 15:48:25","doi":"10.21203/rs.3.rs-7675910/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-30T11:32:01+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-15T14:10:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"22608406471294958146550260079241355797","date":"2025-12-02T09:37:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"194754389731383025238922220848402442981","date":"2025-10-03T19:18:54+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-30T02:21:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"250760508153686141602900164163279274665","date":"2025-09-29T01:56:45+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-28T18:22:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-23T18:15:43+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-23T18:15:32+00:00","index":"","fulltext":""},{"type":"submitted","content":"Clinical Proteomics","date":"2025-09-22T10:10:50+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"clinical-proteomics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"clip","sideBox":"Learn more about [Clinical Proteomics](http://clinicalproteomicsjournal.biomedcentral.com/)","snPcode":"12014","submissionUrl":"https://submission.nature.com/new-submission/12014/3","title":"Clinical Proteomics","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"80efedbd-4067-427a-9ff5-53f8f69751fc","owner":[],"postedDate":"October 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-16T16:01:49+00:00","versionOfRecord":{"articleIdentity":"rs-7675910","link":"https://doi.org/10.1186/s12014-026-09586-4","journal":{"identity":"clinical-proteomics","isVorOnly":false,"title":"Clinical Proteomics"},"publishedOn":"2026-02-11 15:58:58","publishedOnDateReadable":"February 11th, 2026"},"versionCreatedAt":"2025-10-10 15:48:25","video":"","vorDoi":"10.1186/s12014-026-09586-4","vorDoiUrl":"https://doi.org/10.1186/s12014-026-09586-4","workflowStages":[]},"version":"v1","identity":"rs-7675910","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7675910","identity":"rs-7675910","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}