The correlation of Angiopoietin-like protein 7 and ferroptosis-related proteins in patients with metabolic associated fatty liver disease

The correlation of Angiopoietin-like protein 7 and ferroptosis-related proteins in patients with metabolic associated fatty liver disease | 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 The correlation of Angiopoietin-like protein 7 and ferroptosis-related proteins in patients with metabolic associated fatty liver disease Jing Bai, Qian Gao, Yan Liu, Mingming Gao, Yaru Zhou This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7005975/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective The prevalence of metabolic associated fatty liver disease (MAFLD) was increased globally, and data has indicated that ferroptosis participates in the pathogenesis of MAFLD. Angiopoietin-like protein 7 (Angptl 7) is a novel secretory glycoprotein, participating in pathogenesis of many metabolic disorders. However, the role of Angptl 7 playing in MAFLD has been little investigated. Methods A total of 194 participants were enrolled in this study, in which there were 104 MAFLD patients (MAFLD), and 90 healthy controls (CON). Baseline characteristics and serum biochemical parameters were collected. Serum levels of Angptl 7, inflammatory factors and ferroptosis- related proteins were measured by enzyme-linked immunosorbent assay (ELISA). Liver biopsy tissues were obtained from 6 nonalcoholic steatohepatitis participants and the trimmed liver tissues were from 5 healthy liver transplant donors. H&E, Masson, Perls staining and immunohistochemical staining were performed. Results Compared to healthy controls, BMI, SBP and DBP were significantly increased, and serum ALT, AST, TC, TG, LDL-C, GLU, HbA1c, INS, Hcy and UA levels were all significantly increased, while HDL-C was significantly decreased in MAFLD patients (MAFLD vs. CON, P < 0.05 or P < 0.001). Serum Angptl 7, TNF-α, IL-6, ACSL4, Keap-1, HO-1 and Ferritin were significantly increased, while IL-10, GPX4 and Nrf2 were decreased in MAFLD patients when compared to CON group (MAFLD vs. CON, P all < 0.001). Immunohistochemical staining showed that the expression of Angptl 7, Keap-1 and HO-1 were significantly increased, while Nrf2 was significantly decreased in liver tissue from MAFLD group when compared to CON (MAFLD vs. CON, P all < 0.05). ROC analysis showed that Angptl 7 could be as a potential biomarker for diagnosis of MAFLD and the cut-off level was 9.75ng/mL. Conclusion Angptl 7 might participate in the pathogenesis of MAFLD and serum Angptl 7 might be predictive for diagnosis of MAFLD. Angiopoietin-like protein 7 Metabolic associated fatty liver disease Ferroptosis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) [ 1 ], previously known as non-alcoholic fatty liver disease (NAFLD), has been increasing globally [ 2 , 3 ]. Ferroptosis is a novel form of programmed cell death characterized by intracellular iron overload, leading to oxidative stress and lipid peroxidation [ 4 ], which has been recognized to play an important role in the development of MAFLD [ 5 ]. Patients with MAFLD exhibit abnormal iron metabolism and hepatic iron accumulation, and iron chelators could improve liver pathological alterations [ 6 ]. Angiopoietin-like proteins 7 (Angptls 7), a novel secretory glycoprotein, has been found to participate in the pathogenesis of lipid disorder [ 7 ] and T2DM [ 8 ] by promoting oxidative stress [ 9 ]. In addition, evidence has been found that Angptl 7 could induce ferroptosis [ 10 , 11 ] by inhibiting the expression of antioxidant regulator, such as nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) [ 12 , 13 ]. However, whether Angptl 7 participates in MAFLD by inducing ferroptosis has never been investigated. Therefore, the present study aimed to investigate the role of Angptl 7 in MAFLD and its relationship with ferroptosis, which may provide more evidences for MAFLD screening and therapy. Materials and Methods Study Population A total of 194 participants were enrolled from the Physical Examination Center of Hebei Medical University Third Hospital, China, between September 2023 and June 2024, in which there were 104 MAFLD patients (MAFLD) and 90 healthy controls (CON). MALFD was diagnosed by hepatic ultrasonography, which was performed by an experienced sonographer. Diagnosis of fatty liver was established using the standard criteria described previously [ 14 ], which included deep beam attenuation, bright vessel walls, liver to kidney contrast, and parenchymal brightness. Liver biopsy samples were obtained from 6 nonalcoholic steatohepatitis (NASH) patients, and control samples were obtained from the trimmed liver tissues of 5 liver transplant donors. Exclusion criteria were as follows: (1) patients with chronic renal disease; (2) any evidences of active infection (e.g. fever or leukocytosis); (3) acute cardiovascular and cerebrovascular events; (4) acute diabetic complications; (5) patients with missing data; (6) patients refused to provide informed consent. Finally, 194 patients were enrolled in the current study. This study was approved by the Ethics Committee of the Third Hospital of Hebei Medical University (IRB ID: W2024-023-1). The procedures complied with the provisions of the Declaration of Helsinki. Written informed consent was obtained from all participants. Clinical parameters collection Baseline data of participates including systolic blood pressure (SBP) and diastolic blood pressure (DBP) were collected. Data of Fasting serum glucose (FPG), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), aspartate transaminase (AST), alanine transaminase (ALT), serum creatinine (Scr), serum uric acid (UA), Homocysteine (Hcy) and Hemoglobin (HbA1c) were collected from Laboratory of biochemistry. Body mass index (BMI) was calculated using formula: BMI = weight (kg)/height (m) 2 . Measurements of serum Angptl 7, and ferroptosis-related proteins Fasting blood samples were collected and were centrifuged at 1000g for 15 min at 4°C. Serum samples were collected and stored at -80°C. Serum Angptl 7, Keap-1, Nrf2, HO-1, GPX 4, ACSL 4 and Ferritin (FE) levels were measured by ELISA kits accordance with the manufacturer’s instructions. (Shanghai ZCIBIO Technology Co., Ltd; China; No.ZC-55667/ZC-56882/ZC-33257/ ZC-35303/ ZC-54591/ ZC-55786/ ZC-34876). Immunohistochemistry staining of Liver Paraffin section Liver tissues were fixed in 4% neutral formaldehyde, and embedded in paraffin, Slides were deparaffinized, hydrated, and subjected to HE and Masson staining to evaluate the degree of hepatic steatosis, inflammation, and fibrosis. Prussian blue staining was performed for detecting iron and ferritin in tissues. For immunohistochemical staining, slides were deparaffinized, hydrated, and incubated with primary antibodies against Angptl 7 (1:100, 10396-1-AP, ProteintechGroup, China), Nrf2 (1:100, ab62352, Abcam, Cambridge, US), HO-1 (1:100, 10701-1-AP, ProteintechGroup), Keap-1(1:500, 80744-1-RR, ProteintechGroup) overnight at 4℃, then incubated with a horseradish peroxidase (HRP)-conjugated secondary antibody (PV-9001, Beijing Zhongshan Golden Bridge Biotechnology, China) and DAB working solution. Furthermore, image analysis and quantification were performed using the Image FIJI program (Media Cybernetics, National Institutes of Health, US). Statistical Analysis Statistical analysis was performed by SPSS 26.0 software (version26.0, SPSS Inc, Chicago). Data were expressed as mean ± standard deviation (SD). An independent sample t -test was used for statistical analysis between the two groups. For non-normally distributed data, the results were expressed as median and interquartile range [M(p25 ~ p75)], comparisons between groups were performed by non-parametric tests. Categorical data were compared using the chi-square (χ²) test. The influencing factors were analyzed using logistic regression analysis. The receiver operating characteristic (ROC) curve was performed to investigate the diagnostic value of each index in MAFLD. P value of less than 0.05 was considered statistically significant. Results Characteristics of participants There were no significant differences in the gender and age between the two groups (MAFLD vs. CON, P > 0.05). Compared to the CON group, the BMI, SBP, DBP and the levels of ALT, AST, TG, TC, LDL, GLU, HbA1c, INS, UA, and Hcy were significantly increased, while level of HDL-C was significantly decreased in the MAFLD group. (MAFLD vs. CON, P < 0.001 or P < 0.05) (Table 1 ). Table 1 Demographical characteristics of CON and MAFLD subjects Variables CON n = 90 MAFLD n = 104 t/Z/X 2 P Age (years) 41.50 (32.00, 53.50) 45.50 (37.00, 54.00) -1.806 0.071 Gender(male/female) 47/43 55/49 0.008 0.927 BMI (kg/m2) 23.03 ± 2.55 27.03 ± 3.28 − 9.366 < 0.001 SBP (mmHg) 117.32 ± 15.10 124.91 ± 17.65 -3.229 0.001 DBP (mmHg) 73.41 ± 8.73 78.62 ± 11.16 -3.578 < 0.001 PLT ( 109/L) 255 (210.75, 294.08) 245 (212.5, 289.75) -0.058 0.954 ALB ( g/L) 44.02 ± 2.61 43.71 ± 2.12 0.913 0.362 ALT (U/L) 18.00 (12.05, 22.05) 24.65 (17.83, 44.90) -5.227 < 0.001 AST (U/L) 19.70 (17.23, 22.90) 22.25(17.92, 27.98) -2.951 0.003 TBIL (µmol/L) 14.25(10.98, 17.70) 13.50 (10.53, 17.65) -0.518 0.604 DBIL (µmol/L) 2.70 (2.08, 3.50) 2.20(1.70, 3.38) -1.926 0.054 IBIL(µmol/L) 11.30 (8.65, 14.40) 10.90 (8.60, 13.70) -0.108 0.914 TC (mmol/L) 4.44 ± 0.77 5.30 ± 1.11 -6.101 < 0.001 TG (mmol/L) 0.98 (0.79, 1.29) 1.88 (1.35, 2.36) -7.571 < 0.001 HDL-C (mmol/L) 1.23 ± 0.23 1.16 ± 0.21 2.173 0.031 LDL-C (mmol/L) 2.64 ± 0.86 3.34 ± 0.76 -5.955 < 0.001 GLU (mmol/L) 5.12 (4.88, 5.47) 5.61 (5.13, 6.37) -4.917 < 0.001 HbA1c (%) 5.30 (5.10, 5.63) 5.79 (5.30, 6.29) -4.759 < 0.001 INS (mU/L) 1.49 (1.26, 1.81) 3.95 (3.13, 5.28) -10.016 < 0.001 Cr (µmol/L) 71.16 ± 14.47 69.03 ± 14.24 1.032 0.304 UA (µmol/L) 342.37 ± 81.72 381.36 ± 95.41 -3.032 0.003 Hcy (µmol/L) 9.91 (7.78, 12.17) 11.26 (9.94, 13.73) -3.835 < 0.001 The circulating levels of Angptl 7, inflammatory markers and ferroptosis-related proteins in patients with MAFLD Compared to CON group, serum Angptl 7 was significantly higher in MAFLD group (MAFLD vs. CON, P < 0.001). The levels of inflammatory markers TNF-α and IL-6 were significantly increased, while IL-10 was significantly decreased in the MAFLD group when compared to those in CON group (MAFLD vs. CON, P < 0.001), indicating the elevated inflammatory response in MAFLD (Fig. 1 ). Data from this study has also indicated that, compared to healthy controls, the circulation levels of ferroptosis-related proteins such as Keap-1, HO-1, ACSL4, and FE were increased, while Nrf2 and GPX4 were significantly decreased in the MAFLD group (MAFLD vs. CON, P < 0.001), suggesting ferroptosis was involved in MAFLD (Fig. 2 ). Correlation between serum Angptl 7 and other risk factors for MAFLD In this study, serum Angptl 7 was positively correlated with ALT, AST, TC, TG, LDL-C, GLU, HbA1c, INS, UA, TNF-α, and IL-6, while negatively correlated with HDL-C and IL-10, indicating that Angptl 7 associated with inflammation and metabolic factors. Serum Angptl 7 exhibited no correlation with age, gender, PLT, ALB, TBIL, DBIL, IBIL, Cr and Hcy (P > 0.05) (Table 2 ). Table 2 Correlations between serum Angptl 7 level and Biochemical Parameters Variables Correlation coefficient P-value Age 0.125 0.082 Gender 0.063 0.382 BMI 0.479 < 0.001 PLT -0.020 0.775 ALB -0.082 0.257 ALT 0.304 < 0.001 AST 0.185 0.009 TBIL -0.056 0.436 DBIL -0.126 0.081 IBIL -0.012 0.865 TC 0.424 < 0.001 TG 0.492 < 0.001 HDL-C -0.157 0.029 LDL-C 0.386 < 0.001 GLU 0.284 < 0.001 HbA1c 0.296 < 0.001 INS 0.549 < 0.001 Cr -0.064 0.378 UA 0.201 0.005 Hcy 0.129 0.072 TNF-α 0.687 < 0.001 IL-6 0.707 < 0.001 IL-10 -0.635 < 0.001 Serum Angptl 7 was positively correlated with ferroptosis-related proteins ACSL4, Keap-1, HO-1 and FE, and negatively correlated with Nrf2 and GPX4 ( P all < 0.001), indicating that Angptl 7 might correlated with pro-ferroptosis gene profile in MAFLD (Fig. 3 ). Pathological alterations of MAFLD Pathological alterations including hepatocyte macrosteatosis and ballooning, necroinflammation and fibrosis were found in liver samples from NASH patients, in addition, content of iron ions were significantly increased in the hepatic lobules (Fig. 4 ), indicating that iron overload was involved in MAFLD. Compared to the healthy controls, the hepatic expressions of Angptl 7, HO-1 and Keap-1 were significantly increased, while Nrf2 expression was significantly decreased in patients with MAFLD (MAFLD vs CON, P < 0.05) (Fig. 5 ), indicating that elevated Angptl 7 expression and a pro-ferroptosis gene profile were involved in MAFLD. Analysis of risk factors and diagnostic efficacy of MAFLD Data indicated that, serum Angptl 7, GPX4, Keap-1 and HO-1 were independent risk factors for MAFLD with odds ratios (OR) of 3.050, 0.908, 6.417 and 1.441, respectively ( P all < 0.05) (Table 3 , 4 ). Receiver operating characteristic (ROC) curve indicated that serum Angptl 7, GPX 4, Keap-1 and HO-1 all had reliable diagnostic value for diagnosis of MAFLD, with areas under the curve (AUC) of 0.959, 0.839, 0.810 and 0.808 separately, and Angptl 7 exhibited best diagnostic efficacy (Table 5 , Fig. 6 ). Table 3 Traditional risk factors for MAFLD Variables B P OR 95% CI Lower Upper BMI 0.488 < 0.001 1.629 1.407 1.887 SBP 0.028 0.002 1.029 1.010 1.048 DBP 0.052 < 0.001 1.053 1.022 1.086 ALT 0.070 < 0.001 1.073 1.041 1.105 AST 0.082 < 0.001 1.086 1.037 1.137 TC 1.036 < 0.001 2.817 1.922 4.129 TG 1.992 < 0.001 7.330 3.787 14.188 HDL-C -1.418 0.033 0.242 0.066 0.894 LDL-C 1.107 < 0.001 3.024 1.985 4.606 GLU 0.932 < 0.001 2.540 1.635 3.946 HbA1c 1.099 < 0.001 3.002 1.721 5.235 INS 1.653 < 0.001 5.224 3.365 8.110 UA 0.005 0.004 1.005 1.002 1.008 TNF-α 0.755 0.002 2.128 1.333 3.397 IL-6 0.465 < 0.001 1.592 1.348 1.881 Angptl 7 1.040 < 0.001 2.828 2.076 3.851 Keap-1 1.825 < 0.001 6.202 3.646 10.549 HO-1 0.338 < 0.001 1.402 1.265 1.555 GPX4 -0.057 < 0.001 0.945 0.928 0.962 Table 4 Binary multiple logistic regression analysis Variables B S.E. Wald P OR 95% CI Lower Upper Angptl 7 1.147 0.279 16.869 < 0.001 3.149 1.822 5.445 GPX4 -0.103 0.034 9.014 0.003 0.902 0.844 0.965 Keap-1 2.242 0.790 8.050 0.005 9.414 2.000 44.303 HO-1,ng/mL 0.466 0.179 6.811 0.009 1.594 1.123 2.263 Table 5 Diagnostic efficacy analysis in MAFLD Variables Cut-off AUC 95%CI Se, % Sp, % PPV, % NPV, % P Angptl 7 9.75 0.959 0.935–0.983 89.42 88.89 90.29 87.91 < 0.001 GPX4 142.97 0.839 0.786–0.893 62.22 88.46 73.28 75.64 < 0.001 Keap-1 1.96 0.810 0.749–0.869 81.73 71.11 77.36 75.00 < 0.001 HO-1 14.44 0.808 0.746–0.869 80.77 68.89 74.31 72.94 < 0.001 Discussion MAFLD is a hepatic metabolic disorder. Recent studies have indicated that, iron overload and ferroptosis participated in the pathogenesis of MAFLD [ 15 ]. In the present study, we found that the protein level of Angptl 7 was elevated in circulation and liver tissues in MAFLD patients, which associated with increased inflammation, lipid disorders, and elevated pro-ferroptosis related proteins. Serum Angptl 7 possessed diagnostic value for MAFLD. Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has been observed in fatty liver disease both in patients [ 16 , 17 ] and in high-fat diet (HFD) -fed mice models [ 16 , 18 ]. In the present study, we found iron overload both in the blood and liver tissues from patients with MAFLD, and similar results have been described in study performed in MAFLD models[ 16 ]. Study performed by Yang et al in HFD - treated ApoE − / − mice indicated that, in liver tissue, iron transporter TFR1 was upregulated while the expressions of ferroptosis inhibitors Nrf2, SLC7A11 and GPX4 expressions were inhibited [ 15 ]. In NASH patients, HO-1, ACSL4, NF-κB, and IKK β expressions were upregulated while GPX4 expression was significantly reduced in liver biopsy samples when compared to healthy controls[ 16 ]. Therefore, iron deposition and ferroptosis participated in the pathogenesis of MAFLD. Angptl family exhibit structural similarities with angiogenic regulating factors that are known as angiopoietins [ 19 ]. Some Angptl family members, such as Angptl 3 [ 20 ], Angptl 4 [ 21 ] and Angptl 8 [ 22 ] have been found associated with MAFLD. In the present study, we were the first to explore the role of Angtpl 7 in MAFLD, and found that Angtpl 7 protein levels were significantly elevated in liver tissue in patients with MAFLD, indicating elevated hepatic Angtpl 7 expression might participated in the pathogenesis of MAFLD. Evidences have indicated that, Angptl 7 could induce inflammatory response by targeting relative gene expression including Tumor necrosis factor alpha (TNF-α), IL-1β and IL-6 [ 23 ], and induce insulin resistance by downregulation of insulin receptor (INSR) and upregulation of suppressor of cytokine signaling 3 protein (SOCS3) [ 24 ]. Angptl 7 could induce in HUVEC oxidative stress by inhibiting Nrf2/HO-1 signaling pathway [ 25 , 26 ]. Therefore, Angptl 7 might participate in the pathogenesis of MAFLD by promoting inflammatory response and oxidative stress, which also could trigger iron overload and ferroptosis, detailed mechanisms need to be further investigated. In the present study, we found that serum Angptl 7 was elevated and positively correlated with dyslipidemia, inflammation, hepatic dysfunction and ferroptosis- related proteins, which has never been reported before, indicating Angtpl 7 could be a marker for MAFLD-related disorder. Also in this study, we found that serum levels of Angptl 7 processed diagnostic efficacy of MALFD, which might serve as new marker for clinical MAFLD screening. Our study also had some limitations. Firstly, this was a cross-sectional study and no causative relationship between Angptl 7 and MAFLD could be provided. Secondly, this was a single center study with certain sample limitations. Thirdly, the sample size in this study is relatively small, and larger-scale studies will be necessary to further validate the findings of this study. In conclusion, elevated Angptl 7 levels might participated in the pathogenies of MAFLD through promoting ferroptosis. Angptl 7 might serve as a new marker for the diagnosis of MAFLD, which still needs more investigates. Declarations Authors’ contributions JB performed all the experiments. QG, and YL contributed to the collection of human subjects. MG,YL and YZ critically reviewed the study’s design and gave final approval for the version to be published. All authors have read and agreed to the published version of the manuscript. Funding This study was fund by Government-funded Clinical Medicine Outstanding Talent Training Project (No. ZF2024081) and Natural Science Foundation of Hebei Province (No. H2024206030). Data Availability The datasets used during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate The research protocol was approved and supervised by the Ethics Committee of the Third Hospital of Hebei Medical University (approval number: W2024-023-1) and complied with the Principles of the Helsinki Declaration. Written informed consent was obtained from all participants. Consent for publication Not applicable. Competing interests The authors declare no conflict of interest. References Lazarus JV, Mark HE, Allen AM, et al. A global research priority agenda to advance public health responses to fatty liver disease. J Hepatol . 2023 Sep; 79 (3): 618-634. Younossi Z, Tacke F, Arrese M, et al. Global Perspectives on Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Hepatology . 2019 Jun; 69 (6) : 2672- 2682. Huang DQ, El-Serag HB, Loomba R. 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Angiopoietin-like protein 7 promotes an inflammatory phenotype in raw264.7 macrophages through the P38 MAPK signaling pathway. Inflammation. 2016; 39(3):974-85. Xu T, Xu L, Meng P, Ma X, Yang X, Zhou Y, et al. Angptl7 promotes insulin resistance and type 2 diabetes mellitus by multiple mechanisms including SOCS3-mediated IRS1 degradation. FASEB J . 2020; 34(10):13548–13560. Li J, Liang T,Wang Y, et al. Angiopoietin-like protein 7 mediates TNF-a-induced adhesion and oxidative stress in human umbilical vein epithelial cell. Gen Physiol biophysics. 2020;39(3):285–292. Yan R, Lin B, Jin W, et al. NRF2, a Superstar of Ferroptosis. Antioxidants (Basel). 2023 Sep 8;12(9):1739. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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-7005975","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":483494916,"identity":"e1551ec3-8d43-40e3-8486-64f0d3936810","order_by":0,"name":"Jing Bai","email":"","orcid":"","institution":"The Third Hospital of Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"Bai","suffix":""},{"id":483494917,"identity":"3844252e-2649-4e27-a9f1-8551475e37d1","order_by":1,"name":"Qian Gao","email":"","orcid":"","institution":"The Third Hospital of Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qian","middleName":"","lastName":"Gao","suffix":""},{"id":483494918,"identity":"a3b8502c-e845-42ba-b6b5-9f9c398a5540","order_by":2,"name":"Yan Liu","email":"","orcid":"","institution":"The Third Hospital of Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Liu","suffix":""},{"id":483494919,"identity":"1f899eb1-1e84-4bad-b5bf-070d2004eeca","order_by":3,"name":"Mingming Gao","email":"","orcid":"","institution":"Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Mingming","middleName":"","lastName":"Gao","suffix":""},{"id":483494920,"identity":"0da81ef7-22dc-4f92-b770-d53dac49e5b0","order_by":4,"name":"Yaru Zhou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5ElEQVRIiWNgGAWjYLACHgYGOQMQCQSMDcRqMSZdS+IGorXIz8h9JvHmz+H07ey9RzfzMNjIbjjA/OwBPi2MM9LNJOe2Hc7d2XMu7TYPQ5rxhgNs5gb4tDBLpLFJ8zYczt1wI8cMqOVw4oYDPGwS+LSwgbTwAB1mcP8NSMt/wlp4wFrYDicY3OABaTlAWIsEzzNmy7lt6YYbzuSl3ZxjkGw88zCbGV4t8u1pjDfe/LGWNzh+9tiNNxV2sn3Hm5/h1cIgkMACVNAM5YGCihmveiDgP8D8gYGhjpCyUTAKRsEoGMkAAJPHSVqhAd5NAAAAAElFTkSuQmCC","orcid":"","institution":"The Third Hospital of Hebei Medical University","correspondingAuthor":true,"prefix":"","firstName":"Yaru","middleName":"","lastName":"Zhou","suffix":""}],"badges":[],"createdAt":"2025-06-30 03:53:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7005975/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7005975/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":86643040,"identity":"bdb88108-9661-4c67-8ccb-fa2b4bdd6a42","added_by":"auto","created_at":"2025-07-14 08:34:29","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":106676,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe serum levels of Angptl 7 and inflammatory markers in MAFLD patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCompared to CON group, the serum levels of (A) Angptl 7, (B) TNF-α and (C) IL-6 were significantly increased, while (D) IL-10 levels were significantly decreased in the MAFLD group.\u003c/p\u003e\n\u003cp\u003e*\u003cem\u003eP\u0026lt;\u003c/em\u003e0.05, **\u003cem\u003eP\u0026lt;\u003c/em\u003e0.01, ***\u003cem\u003eP\u0026lt;\u003c/em\u003e0.001, ****\u003cem\u003eP\u0026lt;\u003c/em\u003e0.0001, compared to CON group. CON (n=90), MAFLD (n=104)\u003c/p\u003e\n\u003cp\u003eAngptl 7, angiopoietin-like protein 7; TNF-α, tumor necrosis factor-alpha; IL-6, interleukin-6; IL-10, interleukin-10.\u003c/p\u003e","description":"","filename":"Fig01.0600.png","url":"https://assets-eu.researchsquare.com/files/rs-7005975/v1/53a6b71c3ac66d1c371bc2de.png"},{"id":86644668,"identity":"e9845cc6-b89f-4480-8bad-8af8bada8dd8","added_by":"auto","created_at":"2025-07-14 08:42:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":159616,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe serum levels of ferroptosis-related proteins in MAFLD patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCompared to control group, the serum levels of (A) Keap-1 , (C) HO-1, (E) FE and (F) ACSL4 were significantly increased, while (B) Nrf2 and (D) GPX4 levels were significantly decreased.\u003c/p\u003e\n\u003cp\u003e*\u003cem\u003eP\u0026lt;\u003c/em\u003e0.05, **\u003cem\u003eP\u0026lt;\u003c/em\u003e0.01, ***\u003cem\u003eP\u0026lt;\u003c/em\u003e0.001, ****\u003cem\u003eP\u0026lt;\u003c/em\u003e0.0001, compared to CONgroup. CON (n=90), MAFLD (n=104).\u003c/p\u003e\n\u003cp\u003eKeap-1, kelch-like ECH-associated protein 1; Nrf2, nuclear factor erythroid-2-related factor 2; HO- 1, heme oxygenase 1; GPX4, glutathione peroxidase 4; FE, Ferritin; ACSL4, acyl-CoA synthetase long-chain family member 4;\u003c/p\u003e","description":"","filename":"Fig01.0601.png","url":"https://assets-eu.researchsquare.com/files/rs-7005975/v1/7df7e22e292eadfc3868edc3.png"},{"id":86644669,"identity":"9fc49a3b-9024-4922-9280-7a590290d221","added_by":"auto","created_at":"2025-07-14 08:42:30","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":231238,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation analysis of serum Angptl 7 and ferroptosis-related proteins in MAFLD patients.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAngptl 7, angiopoietin-like protein 7; Keap-1, kelch-like ECH-associated protein 1; Nrf2, nuclear factor erythroid-2-related factor 2; HO- 1, heme oxygenase 1; GPX4, glutathione peroxidase 4; FE, Ferritin; ACSL4, acyl-CoA synthetase long-chain family member 4.\u003c/p\u003e","description":"","filename":"Fig01.0602.png","url":"https://assets-eu.researchsquare.com/files/rs-7005975/v1/7386fe32b7865dc7cdbab1bc.png"},{"id":86643047,"identity":"770c81d0-0db0-477d-a1ab-8617399f6056","added_by":"auto","created_at":"2025-07-14 08:34:30","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1623043,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePathological features of liver tissues from MAFLD patients and healthy controls.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePathological alterations including hepatocyte macrosteatosis and ballooning, necroinflammation, fibrosis and iron ions were found in liver samples.\u003c/p\u003e\n\u003cp\u003eH\u0026amp;E staining of liver sections from the CON and MAFLD groups (a). (b) Masson staining, and (c) Prussian blue staining of the liver sections from each group. Data are expressed as mean±SD. *\u003cem\u003eP\u003c/em\u003e\u0026lt;0.05, ****\u003cem\u003eP\u003c/em\u003e\u0026lt;0.0001 vs. CON group. CON (n=5), MAFLD (n=6).\u003c/p\u003e","description":"","filename":"Fig01.0603.png","url":"https://assets-eu.researchsquare.com/files/rs-7005975/v1/8a0f20611d72f0bd344fa047.png"},{"id":86644670,"identity":"e4fc884e-aac0-4754-a18e-d3de32e55e0b","added_by":"auto","created_at":"2025-07-14 08:42:30","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1950112,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eExpression of ferroptosis-related genes in liver tissues.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe expression of Angptl 7, Keap-1 and HO-1 were significantly increased, while Nrf2 was significantly decreased in liver tissue from MAFLD group compared to CON group.\u003c/p\u003e\n\u003cp\u003eMagnification = 20×; scale bar = 100 μm. Data are presented as the mean ± SD.\u003c/p\u003e\n\u003cp\u003e*P\u0026lt;0.05, **P\u0026lt;0.01 vs. CON group. CON (n=5), MAFLD (n=6)\u003c/p\u003e","description":"","filename":"Fig01.0604.png","url":"https://assets-eu.researchsquare.com/files/rs-7005975/v1/6d2c3f349359d6d6f2717a2b.png"},{"id":86643045,"identity":"ce099651-8a79-4904-8650-80053829ce7d","added_by":"auto","created_at":"2025-07-14 08:34:30","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":100587,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eReceiver operator characteristic curve of Angptl 7, GPX4, Keap-1 and HO-1 in the diagnosis of MAFLD.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSerum Angptl 7, GPX 4, Keap-1 and HO-1 all had diagnostic value for diagnosis of MAFLD. CON (n=90), MAFLD (n=104).\u003c/p\u003e\n\u003cp\u003eAngptl 7, angiopoietin-like protein 7; GPX4, glutathione peroxidase 4; Keap-1, kelch-like ECH-associated protein 1; HO- 1, heme oxygenase 1.\u003c/p\u003e","description":"","filename":"Fig01.0605.png","url":"https://assets-eu.researchsquare.com/files/rs-7005975/v1/c08c4d2bd7f0e082f237de21.png"},{"id":87797100,"identity":"957344b0-73dd-4c40-be1b-b720c3f4cb19","added_by":"auto","created_at":"2025-07-29 07:08:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5518681,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7005975/v1/af3193db-1f54-434a-a15a-c586790ac534.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The correlation of Angiopoietin-like protein 7 and ferroptosis-related proteins in patients with metabolic associated fatty liver disease","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], previously known as non-alcoholic fatty liver disease (NAFLD), has been increasing globally [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Ferroptosis is a novel form of programmed cell death characterized by intracellular iron overload, leading to oxidative stress and lipid peroxidation [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], which has been recognized to play an important role in the development of MAFLD [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Patients with MAFLD exhibit abnormal iron metabolism and hepatic iron accumulation, and iron chelators could improve liver pathological alterations [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAngiopoietin-like proteins 7 (Angptls 7), a novel secretory glycoprotein, has been found to participate in the pathogenesis of lipid disorder [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] and T2DM [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] by promoting oxidative stress [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In addition, evidence has been found that Angptl 7 could induce ferroptosis [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] by inhibiting the expression of antioxidant regulator, such as nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, whether Angptl 7 participates in MAFLD by inducing ferroptosis has never been investigated.\u003c/p\u003e\u003cp\u003eTherefore, the present study aimed to investigate the role of Angptl 7 in MAFLD and its relationship with ferroptosis, which may provide more evidences for MAFLD screening and therapy.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cb\u003eStudy Population\u003c/b\u003e\u003c/p\u003e\u003cp\u003e A total of 194 participants were enrolled from the Physical Examination Center of Hebei Medical University Third Hospital, China, between September 2023 and June 2024, in which there were 104 MAFLD patients (MAFLD) and 90 healthy controls (CON).\u003c/p\u003e\u003cp\u003eMALFD was diagnosed by hepatic ultrasonography, which was performed by an experienced sonographer. Diagnosis of fatty liver was established using the standard criteria described previously [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], which included deep beam attenuation, bright vessel walls, liver to kidney contrast, and parenchymal brightness.\u003c/p\u003e\u003cp\u003eLiver biopsy samples were obtained from 6 nonalcoholic steatohepatitis (NASH) patients, and control samples were obtained from the trimmed liver tissues of 5 liver transplant donors.\u003c/p\u003e\u003cp\u003eExclusion criteria were as follows: (1) patients with chronic renal disease; (2) any evidences of active infection (e.g. fever or leukocytosis); (3) acute cardiovascular and cerebrovascular events; (4) acute diabetic complications; (5) patients with missing data; (6) patients refused to provide informed consent. Finally, 194 patients were enrolled in the current study.\u003c/p\u003e\u003cp\u003e This study was approved by the Ethics Committee of the Third Hospital of Hebei Medical University (IRB ID: W2024-023-1). The procedures complied with the provisions of the Declaration of Helsinki. Written informed consent was obtained from all participants.\u003c/p\u003e\u003cp\u003e\u003cb\u003eClinical parameters collection\u003c/b\u003e\u003c/p\u003e\u003cp\u003eBaseline data of participates including systolic blood pressure (SBP) and diastolic blood pressure (DBP) were collected. Data of Fasting serum glucose (FPG), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), aspartate transaminase (AST), alanine transaminase (ALT), serum creatinine (Scr), serum uric acid (UA), Homocysteine (Hcy) and Hemoglobin (HbA1c) were collected from Laboratory of biochemistry. Body mass index (BMI) was calculated using formula: BMI\u0026thinsp;=\u0026thinsp;weight (kg)/height (m)\u003csup\u003e2\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMeasurements of serum Angptl 7, and ferroptosis-related proteins\u003c/b\u003e\u003c/p\u003e\u003cp\u003eFasting blood samples were collected and were centrifuged at 1000g for 15 min at 4\u0026deg;C. Serum samples were collected and stored at -80\u0026deg;C. Serum Angptl 7, Keap-1, Nrf2, HO-1, GPX 4, ACSL 4 and Ferritin (FE) levels were measured by ELISA kits accordance with the manufacturer\u0026rsquo;s instructions. (Shanghai ZCIBIO Technology Co., Ltd; China; No.ZC-55667/ZC-56882/ZC-33257/ ZC-35303/ ZC-54591/ ZC-55786/ ZC-34876).\u003c/p\u003e\u003cp\u003e\u003cb\u003eImmunohistochemistry staining of Liver Paraffin section\u003c/b\u003e\u003c/p\u003e\u003cp\u003eLiver tissues were fixed in 4% neutral formaldehyde, and embedded in paraffin, Slides were deparaffinized, hydrated, and subjected to HE and Masson staining to evaluate the degree of hepatic steatosis, inflammation, and fibrosis. Prussian blue staining was performed for detecting iron and ferritin in tissues.\u003c/p\u003e\u003cp\u003eFor immunohistochemical staining, slides were deparaffinized, hydrated, and incubated with primary antibodies against Angptl 7 (1:100, 10396-1-AP, ProteintechGroup, China), Nrf2 (1:100, ab62352, Abcam, Cambridge, US), HO-1 (1:100, 10701-1-AP, ProteintechGroup), Keap-1(1:500, 80744-1-RR, ProteintechGroup) overnight at 4℃, then incubated with a horseradish peroxidase (HRP)-conjugated secondary antibody (PV-9001, Beijing Zhongshan Golden Bridge Biotechnology, China) and DAB working solution. Furthermore, image analysis and quantification were performed using the Image FIJI program (Media Cybernetics, National Institutes of Health, US).\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eStatistical analysis was performed by SPSS 26.0 software (version26.0, SPSS Inc, Chicago). Data were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD). An independent sample \u003cem\u003et\u003c/em\u003e-test was used for statistical analysis between the two groups. For non-normally distributed data, the results were expressed as median and interquartile range [M(p25\u0026thinsp;~\u0026thinsp;p75)], comparisons between groups were performed by non-parametric tests. Categorical data were compared using the chi-square (χ\u0026sup2;) test. The influencing factors were analyzed using logistic regression analysis. The receiver operating characteristic (ROC) curve was performed to investigate the diagnostic value of each index in MAFLD. P value of less than 0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003eCharacteristics of participants\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThere were no significant differences in the gender and age between the two groups (MAFLD vs. CON, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Compared to the CON group, the BMI, SBP, DBP and the levels of ALT, AST, TG, TC, LDL, GLU, HbA1c, INS, UA, and Hcy were significantly increased, while level of HDL-C was significantly decreased in the MAFLD group. (MAFLD vs. CON, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001 or \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDemographical characteristics of CON and MAFLD subjects\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCON\u003c/p\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;90\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMAFLD\u003c/p\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;104\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003et/Z/X\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e41.50 (32.00, 53.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e45.50 (37.00, 54.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-1.806\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.071\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGender(male/female)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e47/43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e55/49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.008\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.927\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBMI (kg/m2)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23.03\u0026thinsp;\u0026plusmn;\u0026thinsp;2.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e27.03\u0026thinsp;\u0026plusmn;\u0026thinsp;3.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026minus;\u0026thinsp;9.366\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSBP (mmHg)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e117.32\u0026thinsp;\u0026plusmn;\u0026thinsp;15.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e124.91\u0026thinsp;\u0026plusmn;\u0026thinsp;17.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-3.229\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDBP (mmHg)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e73.41\u0026thinsp;\u0026plusmn;\u0026thinsp;8.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e78.62\u0026thinsp;\u0026plusmn;\u0026thinsp;11.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-3.578\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePLT ( 109/L)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e255 (210.75, 294.08)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e245 (212.5, 289.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.058\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.954\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eALB ( g/L)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e44.02\u0026thinsp;\u0026plusmn;\u0026thinsp;2.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e43.71\u0026thinsp;\u0026plusmn;\u0026thinsp;2.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.913\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.362\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eALT (U/L)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e18.00 (12.05, 22.05)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24.65 (17.83, 44.90)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-5.227\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAST (U/L)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19.70 (17.23, 22.90)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22.25(17.92, 27.98)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-2.951\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.003\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTBIL (\u0026micro;mol/L)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14.25(10.98, 17.70)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13.50 (10.53, 17.65)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.518\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.604\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDBIL (\u0026micro;mol/L)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.70 (2.08, 3.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.20(1.70, 3.38)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-1.926\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.054\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eIBIL(\u0026micro;mol/L)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11.30 (8.65, 14.40)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10.90 (8.60, 13.70)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-0.108\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.914\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTC (mmol/L)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.44\u0026thinsp;\u0026plusmn;\u0026thinsp;0.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.30\u0026thinsp;\u0026plusmn;\u0026thinsp;1.11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-6.101\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTG (mmol/L)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.98 (0.79, 1.29)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.88 (1.35, 2.36)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-7.571\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHDL-C (mmol/L)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.16\u0026thinsp;\u0026plusmn;\u0026thinsp;0.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.173\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.031\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLDL-C (mmol/L)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.64\u0026thinsp;\u0026plusmn;\u0026thinsp;0.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.34\u0026thinsp;\u0026plusmn;\u0026thinsp;0.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-5.955\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGLU (mmol/L)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.12 (4.88, 5.47)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.61 (5.13, 6.37)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-4.917\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHbA1c (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.30 (5.10, 5.63)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.79 (5.30, 6.29)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-4.759\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eINS (mU/L)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.49 (1.26, 1.81)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.95 (3.13, 5.28)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-10.016\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCr (\u0026micro;mol/L)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e71.16\u0026thinsp;\u0026plusmn;\u0026thinsp;14.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e69.03\u0026thinsp;\u0026plusmn;\u0026thinsp;14.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.032\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.304\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eUA (\u0026micro;mol/L)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e342.37\u0026thinsp;\u0026plusmn;\u0026thinsp;81.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e381.36\u0026thinsp;\u0026plusmn;\u0026thinsp;95.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-3.032\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.003\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHcy (\u0026micro;mol/L)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9.91 (7.78, 12.17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11.26 (9.94, 13.73)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-3.835\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eThe circulating levels of Angptl 7, inflammatory markers and ferroptosis-related proteins in patients with MAFLD\u003c/b\u003e\u003c/p\u003e\u003cp\u003eCompared to CON group, serum Angptl 7 was significantly higher in MAFLD group (MAFLD vs. CON, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The levels of inflammatory markers TNF-α and IL-6 were significantly increased, while IL-10 was significantly decreased in the MAFLD group when compared to those in CON group (MAFLD vs. CON, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), indicating the elevated inflammatory response in MAFLD (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eData from this study has also indicated that, compared to healthy controls, the circulation levels of ferroptosis-related proteins such as Keap-1, HO-1, ACSL4, and FE were increased, while Nrf2 and GPX4 were significantly decreased in the MAFLD group (MAFLD vs. CON, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), suggesting ferroptosis was involved in MAFLD (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eCorrelation between serum Angptl 7 and other risk factors for MAFLD\u003c/b\u003e\u003c/p\u003e\u003cp\u003eIn this study, serum Angptl 7 was positively correlated with ALT, AST, TC, TG, LDL-C, GLU, HbA1c, INS, UA, TNF-α, and IL-6, while negatively correlated with HDL-C and IL-10, indicating that Angptl 7 associated with inflammation and metabolic factors. Serum Angptl 7 exhibited no correlation with age, gender, PLT, ALB, TBIL, DBIL, IBIL, Cr and Hcy (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCorrelations between serum Angptl 7 level and Biochemical Parameters\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCorrelation\u003c/p\u003e\u003cp\u003ecoefficient\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eP-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.125\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.082\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.063\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.382\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBMI\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.479\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePLT\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.775\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eALB\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.082\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.257\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eALT\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.304\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAST\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.185\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.009\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTBIL\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.056\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.436\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDBIL\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.126\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.081\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eIBIL\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.012\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.865\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTC\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.424\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTG\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.492\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHDL-C\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.157\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.029\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLDL-C\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.386\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGLU\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.284\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHbA1c\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.296\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eINS\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.549\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCr\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.064\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.378\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eUA\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.201\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHcy\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.129\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.072\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTNF-α\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.687\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eIL-6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.707\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eIL-10\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.635\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eSerum Angptl 7 was positively correlated with ferroptosis-related proteins ACSL4, Keap-1, HO-1 and FE, and negatively correlated with Nrf2 and GPX4 ( \u003cem\u003eP all\u003c/em\u003e \u0026lt;\u0026thinsp;0.001), indicating that Angptl 7 might correlated with pro-ferroptosis gene profile in MAFLD (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003ePathological alterations of MAFLD\u003c/b\u003e\u003c/p\u003e\u003cp\u003ePathological alterations including hepatocyte macrosteatosis and ballooning, necroinflammation and fibrosis were found in liver samples from NASH patients, in addition, content of iron ions were significantly increased in the hepatic lobules (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e), indicating that iron overload was involved in MAFLD.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eCompared to the healthy controls, the hepatic expressions of Angptl 7, HO-1 and Keap-1 were significantly increased, while Nrf2 expression was significantly decreased in patients with MAFLD (MAFLD vs CON, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e), indicating that elevated Angptl 7 expression and a pro-ferroptosis gene profile were involved in MAFLD.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eAnalysis of risk factors and diagnostic efficacy of MAFLD\u003c/b\u003e\u003c/p\u003e\u003cp\u003eData indicated that, serum Angptl 7, GPX4, Keap-1 and HO-1 were independent risk factors for MAFLD with odds ratios (OR) of 3.050, 0.908, 6.417 and 1.441, respectively (\u003cem\u003eP\u003c/em\u003e all \u0026lt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Receiver operating characteristic (ROC) curve indicated that serum Angptl 7, GPX 4, Keap-1 and HO-1 all had reliable diagnostic value for diagnosis of MAFLD, with areas under the curve (AUC) of 0.959, 0.839, 0.810 and 0.808 separately, and Angptl 7 exhibited best diagnostic efficacy (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eTraditional risk factors for MAFLD\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eOR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLower\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eUpper\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBMI\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.488\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.629\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.407\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.887\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSBP\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.028\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.029\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.010\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.048\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDBP\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.052\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.053\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.086\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eALT\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.070\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.073\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.041\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.105\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAST\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.082\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.086\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.037\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.137\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTC\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.036\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.817\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.922\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e4.129\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTG\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.992\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e7.330\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3.787\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e14.188\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHDL-C\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-1.418\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.033\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.242\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.066\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.894\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLDL-C\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.107\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3.024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.985\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e4.606\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGLU\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.932\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.540\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.635\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e3.946\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHbA1c\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.099\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3.002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.721\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e5.235\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eINS\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.653\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5.224\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3.365\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e8.110\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eUA\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.005\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.008\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTNF-α\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.755\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.128\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.333\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e3.397\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eIL-6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.465\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.592\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.348\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.881\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAngptl 7\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.040\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.828\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.076\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e3.851\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eKeap-1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.825\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6.202\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3.646\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e10.549\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHO-1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.338\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.402\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.265\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.555\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGPX4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.057\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.945\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.928\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.962\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBinary multiple logistic regression analysis\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eS.E.\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eWald\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eOR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLower\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eUpper\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAngptl 7\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.147\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.279\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e16.869\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e3.149\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1.822\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e5.445\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGPX4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.103\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.034\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e9.014\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.003\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.902\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.844\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.965\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eKeap-1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2.242\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.790\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e8.050\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e9.414\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e2.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e44.303\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHO-1,ng/mL\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.466\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.179\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6.811\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.009\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.594\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1.123\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e2.263\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDiagnostic efficacy analysis in MAFLD\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCut-off\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAUC\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e95%CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSe, %\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSp, %\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePPV, %\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNPV, %\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAngptl 7\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e9.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.959\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.935\u0026ndash;0.983\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e89.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e88.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e90.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e87.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGPX4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e142.97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.839\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.786\u0026ndash;0.893\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e62.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e88.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e73.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e75.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eKeap-1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.96\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.810\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.749\u0026ndash;0.869\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e81.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e71.11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e77.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e75.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHO-1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e14.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.808\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.746\u0026ndash;0.869\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e80.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e68.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e74.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e72.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eMAFLD is a hepatic metabolic disorder. Recent studies have indicated that, iron overload and ferroptosis participated in the pathogenesis of MAFLD [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In the present study, we found that the protein level of Angptl 7 was elevated in circulation and liver tissues in MAFLD patients, which associated with increased inflammation, lipid disorders, and elevated pro-ferroptosis related proteins. Serum Angptl 7 possessed diagnostic value for MAFLD.\u003c/p\u003e\u003cp\u003eFerroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has been observed in fatty liver disease both in patients [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] and in high-fat diet (HFD) -fed mice models [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In the present study, we found iron overload both in the blood and liver tissues from patients with MAFLD, and similar results have been described in study performed in MAFLD models[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Study performed by Yang et al in HFD - treated ApoE \u003csup\u003e\u0026minus; / \u0026minus;\u003c/sup\u003e mice indicated that, in liver tissue, iron transporter TFR1 was upregulated while the expressions of ferroptosis inhibitors Nrf2, SLC7A11 and GPX4 expressions were inhibited [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In NASH patients, HO-1, ACSL4, NF-κB, and IKK β expressions were upregulated while GPX4 expression was significantly reduced in liver biopsy samples when compared to healthy controls[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Therefore, iron deposition and ferroptosis participated in the pathogenesis of MAFLD.\u003c/p\u003e\u003cp\u003eAngptl family exhibit structural similarities with angiogenic regulating factors that are known as angiopoietins [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Some Angptl family members, such as Angptl 3 [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], Angptl 4 [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] and Angptl 8 [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] have been found associated with MAFLD. In the present study, we were the first to explore the role of Angtpl 7 in MAFLD, and found that Angtpl 7 protein levels were significantly elevated in liver tissue in patients with MAFLD, indicating elevated hepatic Angtpl 7 expression might participated in the pathogenesis of MAFLD. Evidences have indicated that, Angptl 7 could induce inflammatory response by targeting relative gene expression including Tumor necrosis factor alpha (TNF-α), IL-1β and IL-6 [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], and induce insulin resistance by downregulation of insulin receptor (INSR) and upregulation of suppressor of cytokine signaling 3 protein (SOCS3) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Angptl 7 could induce in HUVEC oxidative stress by inhibiting Nrf2/HO-1 signaling pathway [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Therefore, Angptl 7 might participate in the pathogenesis of MAFLD by promoting inflammatory response and oxidative stress, which also could trigger iron overload and ferroptosis, detailed mechanisms need to be further investigated.\u003c/p\u003e\u003cp\u003eIn the present study, we found that serum Angptl 7 was elevated and positively correlated with dyslipidemia, inflammation, hepatic dysfunction and ferroptosis- related proteins, which has never been reported before, indicating Angtpl 7 could be a marker for MAFLD-related disorder. Also in this study, we found that serum levels of Angptl 7 processed diagnostic efficacy of MALFD, which might serve as new marker for clinical MAFLD screening.\u003c/p\u003e\u003cp\u003eOur study also had some limitations. Firstly, this was a cross-sectional study and no causative relationship between Angptl 7 and MAFLD could be provided. Secondly, this was a single center study with certain sample limitations. Thirdly, the sample size in this study is relatively small, and larger-scale studies will be necessary to further validate the findings of this study.\u003c/p\u003e\u003cp\u003eIn conclusion, elevated Angptl 7 levels might participated in the pathogenies of MAFLD through promoting ferroptosis. Angptl 7 might serve as a new marker for the diagnosis of MAFLD, which still needs more investigates.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJB performed all the experiments. QG, and YL contributed to the collection of human subjects. MG,YL and YZ critically reviewed the study\u0026rsquo;s design and gave final approval for the version to be published. All authors have read and agreed to the published version of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was fund by Government-funded Clinical Medicine Outstanding Talent Training Project (No. ZF2024081) and Natural Science Foundation of Hebei Province (No. H2024206030).\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used during the current study are available from the corresponding author on reasonable request. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe research protocol was approved and supervised by the Ethics Committee of the Third Hospital of Hebei Medical University (approval number: W2024-023-1) and complied with the Principles of the Helsinki Declaration. Written informed consent was obtained from all participants.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eLazarus JV, Mark HE, Allen AM, et al. A global research priority agenda to advance public health responses to fatty liver disease.\u0026nbsp;\u003cem\u003eJ Hepatol\u003c/em\u003e\u003cem\u003e.\u0026nbsp;\u003c/em\u003e2023 Sep; 79 (3): 618-634.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eYounossi Z, Tacke F, Arrese M, et al. 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Angptl7 promotes insulin resistance and type 2 diabetes mellitus by multiple mechanisms including SOCS3-mediated IRS1 degradation.\u0026nbsp;\u003cem\u003eFASEB J.\u003c/em\u003e 2020; 34(10):13548\u0026ndash;13560.\u003c/li\u003e\n \u003cli\u003eQian T, Wang K, Cui J, He Y, Yang Z. Angiopoietin-like protein 7 promotes an inflammatory phenotype in raw264.7 macrophages through the P38 MAPK signaling pathway.\u0026nbsp;\u003cem\u003eInflammation.\u003c/em\u003e 2016; 39(3):974-85.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eXue F, Jiang J, Kou J. Screening of key genes related to ferroptosis and a molecular interaction network analysis in colorectal cancer using machine learning and bioinformatics.\u0026nbsp;\u003cem\u003eJ Gastrointest Oncol.\u0026nbsp;\u003c/em\u003e2023 Jun 30;14(3):1346-1359.\u003c/li\u003e\n \u003cli\u003eLiu H, Xiang C, Wang Z, Song Y. 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Ultrasound scanning in the detection of hepatic fibrosis and steatosis.\u0026nbsp;\u003cem\u003eBr Med J (Clin Res Ed).\u0026nbsp;\u003c/em\u003e1986; 292: 13-5.\u003c/li\u003e\n \u003cli\u003eYang Y, Chen J, Gao Q, et al. Study on the attenuated effect of Ginkgolide B on ferroptosis in high fat diet induced nonalcoholic fatty liver disease.\u0026nbsp;\u003cem\u003eToxicology.\u0026nbsp;\u003c/em\u003e2020 Dec 1; 445:152599.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eYuan X, Li L, Zhang Y, et al. Heme oxygenase 1 alleviates nonalcoholic steatohepatitis by suppressing hepatic ferroptosis.\u0026nbsp;\u003cem\u003eLipids Health Dis.\u003c/em\u003e 2023 Jul 8; 22(1):99.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eCai W, Wu S, Ming X, et al. IL6 Derived from Macrophages under Intermittent Hypoxia Exacerbates NAFLD by Promoting Ferroptosis via MARCH3-Led Ubiquitylation of GPX4.\u0026nbsp;\u003cem\u003eAdv Sci (Weinh).\u003c/em\u003e 2024 Nov;11(41):e2402241.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eTong J, Lan XT, Zhang Z, et al. Ferroptosis inhibitor liproxstatin-1 alleviates metabolic dysfunction-associated fatty liver disease in mice: potential involvement of PANoptosis.\u0026nbsp;\u003cem\u003eActa Pharmacol Sin.\u0026nbsp;\u003c/em\u003e2023 May;44(5):1014-1028.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eKadomatsu T, Tabata M, Oike Y. Angiopoietin-like proteins: emerging targets for treatment of obesity and related metabolic diseases.\u0026nbsp;\u003cem\u003eFEBS J.\u003c/em\u003e2011; 278: 559-64.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eYilmaz Y, Ulukaya E, Atug O, Dolar E. Serum concentrations of human angiopoietin-like protein 3 in patients with nonalcoholic fatty liver disease: association with insulin resistance.\u0026nbsp;\u003cem\u003eEur J Gastroenterol Hepatol.\u0026nbsp;\u003c/em\u003e2009 Nov; 21 (11) : 1247-51.\u003c/li\u003e\n \u003cli\u003eAltun \u0026Ouml;, Dikker O, Arman Y, et al. Serum Angiopoietin-like peptide 4 levels in patients with hepatic steatosis.\u0026nbsp;\u003cem\u003eCytokine.\u0026nbsp;\u003c/em\u003e2018 Nov;111:496-499.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eLee YH, Lee SG, Lee CJ, et al. Association between betatrophin/ANGPTL8 and non-alcoholic fatty liver disease: animal and human studies.\u0026nbsp;\u003cem\u003eSci Rep.\u003c/em\u003e 2016 Apr 5;6: 24013.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eQian T, Wang K, Cui J, He Y, Yang Z. Angiopoietin-like protein 7 promotes an inflammatory phenotype in raw264.7 macrophages through the P38 MAPK signaling pathway.\u0026nbsp;\u003cem\u003eInflammation.\u0026nbsp;\u003c/em\u003e2016; 39(3):974-85.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eXu T, Xu L, Meng P, Ma X, Yang X, Zhou Y, et al. Angptl7 promotes insulin resistance and type 2 diabetes mellitus by multiple mechanisms including SOCS3-mediated IRS1 degradation.\u0026nbsp;\u003cem\u003eFASEB J\u003c/em\u003e. 2020; 34(10):13548\u0026ndash;13560.\u003c/li\u003e\n \u003cli\u003eLi J, Liang T,Wang Y, et al. Angiopoietin-like protein 7 mediates TNF-a-induced adhesion and oxidative stress in human umbilical vein epithelial cell.\u0026nbsp;\u003cem\u003eGen Physiol biophysics.\u003c/em\u003e 2020;39(3):285\u0026ndash;292.\u003c/li\u003e\n \u003cli\u003eYan R, Lin B, Jin W, et al. NRF2, a Superstar of Ferroptosis.\u0026nbsp;\u003cem\u003eAntioxidants (Basel).\u003c/em\u003e 2023 Sep 8;12(9):1739.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Angiopoietin-like protein 7, Metabolic associated fatty liver disease, Ferroptosis","lastPublishedDoi":"10.21203/rs.3.rs-7005975/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7005975/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eThe prevalence of metabolic associated fatty liver disease (MAFLD) was increased globally, and data has indicated that ferroptosis participates in the pathogenesis of MAFLD. Angiopoietin-like protein 7 (Angptl 7) is a novel secretory glycoprotein, participating in pathogenesis of many metabolic disorders. However, the role of Angptl 7 playing in MAFLD has been little investigated.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA total of 194 participants were enrolled in this study, in which there were 104 MAFLD patients (MAFLD), and 90 healthy controls (CON). Baseline characteristics and serum biochemical parameters were collected. Serum levels of Angptl 7, inflammatory factors and ferroptosis- related proteins were measured by enzyme-linked immunosorbent assay (ELISA). Liver biopsy tissues were obtained from 6 nonalcoholic steatohepatitis participants and the trimmed liver tissues were from 5 healthy liver transplant donors. H\u0026amp;E, Masson, Perls staining and immunohistochemical staining were performed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eCompared to healthy controls, BMI, SBP and DBP were significantly increased, and serum ALT, AST, TC, TG, LDL-C, GLU, HbA1c, INS, Hcy and UA levels were all significantly increased, while HDL-C was significantly decreased in MAFLD patients (MAFLD vs. CON, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 or P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Serum Angptl 7, TNF-α, IL-6, ACSL4, Keap-1, HO-1 and Ferritin were significantly increased, while IL-10, GPX4 and Nrf2 were decreased in MAFLD patients when compared to CON group (MAFLD vs. CON, P all \u0026lt;\u0026thinsp;0.001). Immunohistochemical staining showed that the expression of Angptl 7, Keap-1 and HO-1 were significantly increased, while Nrf2 was significantly decreased in liver tissue from MAFLD group when compared to CON (MAFLD vs. CON, P all \u0026lt;\u0026thinsp;0.05). ROC analysis showed that Angptl 7 could be as a potential biomarker for diagnosis of MAFLD and the cut-off level was 9.75ng/mL.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eAngptl 7 might participate in the pathogenesis of MAFLD and serum Angptl 7 might be predictive for diagnosis of MAFLD.\u003c/p\u003e","manuscriptTitle":"The correlation of Angiopoietin-like protein 7 and ferroptosis-related proteins in patients with metabolic associated fatty liver disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-14 08:34:25","doi":"10.21203/rs.3.rs-7005975/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"af8bb101-55ca-4593-845a-ca1062cf2aeb","owner":[],"postedDate":"July 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-29T07:08:16+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-14 08:34:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7005975","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7005975","identity":"rs-7005975","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}