Serum Metabolomics Reveals Metabolic Reprofiling and Perturbed Pathways after Aortic Dissection Surgery

Serum Metabolomics Reveals Metabolic Reprofiling and Perturbed Pathways after Aortic Dissection Surgery | 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 Serum Metabolomics Reveals Metabolic Reprofiling and Perturbed Pathways after Aortic Dissection Surgery Yuji Xiao, Jia Liu, Yaoguang Feng, Juan Wu, Wanru Ma, Haonan Zhang, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7708816/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 To apply untargeted metabolomics technology to systematically analyze changes in the serum metabolic profiles of patients after surgery for acute DeBakey type I aortic dissection, aiming to explore postoperative metabolic characteristics and evaluate their potential application value. Methods This study enrolled 30 postoperative patients (AT) and 30 healthy controls (HC). Metabolite detection was performed using ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS). After strict quality control, multivariate statistical analysis was employed to screen for differential metabolites, followed by KEGG pathway enrichment and topological analysis. The discriminatory performance of key metabolites was assessed using receiver operating characteristic (ROC) curves. Results A total of 791 differential metabolites were identified. The metabolic profiles showed significant separation between the postoperative and healthy control groups. The differential metabolites were primarily enriched in pathways such as aminoacyl-tRNA biosynthesis, glycine/serine/threonine metabolism, and ABC transporters. Several metabolites exhibited promising discriminatory power. Conclusion This study reveals extensive metabolic reprogramming following aortic dissection surgery, indicating synergistic perturbations in amino acid metabolism, energy metabolism, and membrane transport pathways. The identified metabolic features provide a potential molecular basis for postoperative metabolic monitoring. Aortic dissection surgery Postoperative metabolism Untargeted metabolomics Metabolic reprogramming KEGG pathway Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Introduction Aortic dissection is a critical cardiovascular condition characterized by sudden onset and rapid progression. Particularly in acute DeBakey type I dissection, mortality increases by 1–2% per hour [ 1 ]. Modern surgical techniques, such as Sun’s procedure and deep hypothermic circulatory arrest, represent the most effective treatment strategies currently available. However, the extensive surgical trauma and prolonged cardiopulmonary bypass often induce severe metabolic disturbances in patients postoperatively, significantly impacting clinical outcomes [ 2 , 3 ]. Nevertheless, systematic research on metabolic alterations following aortic dissection surgery remains exceedingly limited. The metabolic regulatory mechanisms underlying vascular repair have yet to be elucidated, and there is a notable clinical absence of efficient, specific biomarkers for the precise assessment and intervention of postoperative metabolic status [ 4 , 5 ]. These gaps considerably constrain the optimization of postoperative management strategies and the improvement of long-term quality of life for patients. Metabolomics, a major branch of systems biology, provides a comprehensive reflection of the dynamic changes of small-molecule metabolites within organisms, offering a powerful tool for investigating disease mechanisms and discovering biomarkers. In recent years, metabolomics has demonstrated broad application prospects in the field of cardiovascular diseases, such as elucidating metabolic features in heart failure and ischemic heart disease [ 6 , 7 ]. Nevertheless, research on metabolic reprogramming in patients following aortic dissection surgery remains in its infancy, particularly regarding the mechanisms by which surgical stress perturbs metabolic networks. Furthermore, the association between postoperative metabolic disturbances and clinical outcomes—such as organ function recovery and the occurrence of complications — has yet to be thoroughly explored. Therefore, elucidating the mechanisms of vascular repair from the perspective of metabolic regulation and developing targeted therapeutic strategies represent critical breakthroughs for improving patient prognosis [ 8 , 9 ], holding significant clinical importance for long-term outcomes. To address this research gap, we applied untargeted metabolomics to systematically analyze the serum metabolic profiles of patients following surgery for acute DeBakey type I aortic dissection compared with healthy controls. Our study aims not only to identify potential biomarkers that accurately reflect postoperative metabolic status but, more importantly, to uncover key pathways and network interaction mechanisms underlying postoperative metabolic disturbances. The findings of this research are expected to provide novel insights into postoperative metabolic stress and establish a theoretical foundation for developing targeted metabolic interventions to improve patient outcomes. Materials and Methods Data Collection Serum samples were collected from 30 postoperative patients with acute DeBakey type I aortic dissection who were admitted to the Department of Cardiothoracic and Vascular Surgery at the First Affiliated Hospital of University of South China between July and December 2024, along with 30 healthy controls recruited during the same period. All samples were obtained following a standardized protocol: peripheral venous blood was drawn from postoperative patients on the first daytime after surgery, while samples from healthy controls were collected uniformly during daytime hours.A volume of 2–5 mL of blood was collected using additive-free specialized blood collection tubes. After ensuring complete evaporation of disinfectants, samples were gently inverted to mix and allowed to clot at room temperature for 1 hour. All samples were transported by dedicated personnel and labeled with patient names and hospital identification numbers to ensure traceability. Upon receipt, samples were immediately stored at − 80°C until further analysis. This standardized collection procedure effectively minimized anticoagulant interference and hemolysis risk, thereby ensuring high-quality serum samples for subsequent metabolomic analysis. The study protocol and sample collection procedures strictly adhered to the principles of the Declaration of Helsinki and were reviewed and approved by the Medical Ethics Committee of the First Affiliated Hospital of University of South China (Approval No: 2024LL1016001). Prior to participation, all enrolled patients with acute DeBakey type I aortic dissection or their legally authorized representatives provided written informed consent after full explanation of the study. The entire study was subject to ongoing supervision by the ethics committee, with no protocol deviations or ethical disputes occurring. Eligibility Criteria Patients diagnosed with acute Stanford type A aortic dissection based on imaging and clinical manifestations were included, provided they met the surgical indication criteria as per the 2022 ESC Guidelines for the Diagnosis and Treatment of Aortic Diseases. Exclusion criteria comprised preoperative impaired consciousness or coma, defined as a Glasgow Coma Scale score ≤ 8; the presence of multiple organ dysfunction syndrome meeting at least two organ failure criteria; or the requirement for sustained high-dose vasoactive drug support—such as norepinephrine exceeding 0.5 µg/kg/min for a duration of 24 hours or longer—to maintain circulatory stability. Experimental Procedures Metabolite Extraction Metabolites were extracted using a Starlid™ workstation. A volume of 50 µL of each sample was mixed with 200 µL of extraction solution (methanol:acetonitrile = 1:1, v/v, containing internal standards) and oscillated at 750 rpm for 5 minutes. After standing for another 5 minutes, the mixture was filtered through a protein precipitation plate, and the filtrate was collected. Quality control (QC) samples were prepared by pooling equal volumes of all sample filtrates. LC-MS/MS Analysis For polar metabolites, LC-MS/MS analysis was performed using a Vanquish UHPLC system (Thermo Fisher Scientific) [ 10 ] equipped with a Waters ACQUITY UPLC BEH Amide column (2.1 mm × 50 mm, 1.7 µm) and coupled to an Orbitrap Exploris 120 mass spectrometer (Thermo Fisher). The mobile phase consisted of 25 mmol/L ammonium acetate and 25 mmol/L ammonia aqueous solution (pH = 9.75) (phase A) and acetonitrile (phase B). The autosampler temperature was maintained at 4°C, and the injection volume was 2 µL. The Orbitrap Exploris 120 mass spectrometer was operated in information-dependent acquisition (IDA) mode, controlled by the acquisition software (Xcalibur, Thermo Fisher), which continuously evaluated full-scan MS spectra to trigger MS/MS acquisition. The electrospray ionization (ESI) source conditions were set as follows: sheath gas flow rate, 50 Arb; auxiliary gas flow rate, 15 Arb; capillary temperature, 320°C; full MS resolution, 60,000; MS/MS resolution, 15,000; collision energy using stepped normalized collision energy (SNCE) at 20, 30, and 40 eV; and spray voltages of 3.8 kV (positive ion mode) and 3.4 kV (negative ion mode). Data Preprocessing and Annotation Raw data were converted to mzXML format using ProteoWizard and processed with an in-house R-based pipeline built upon the XCMS package for feature detection, extraction, alignment, and integration. Metabolite identification was performed using R packages and AigenXDB (version 3.0). Reference: Zhou, Z., Luo, M., Zhang, H., Yin, Y., Cai, Y., & Zhu, Z. J. (2022).Metabolite annotation from knowns to unknowns through knowledgeguided multi-layer metabolic networking. Nature communications, 13(1),6656. Quality Control QC samples were employed to systematically monitor the reliability and reproducibility of the analytical process. The QC samples were prepared by pooling equal volumes of all experimental samples and were injected at intervals of every 10 experimental samples to assess instrumental drift and systematic error. The stability of the LC-MS system was evaluated by examining the extracted ion chromatograms (EICs) of isotopic internal standards in the QC samples, which allowed for assessment of retention time consistency and response stability. Potential system contamination was evaluated by comparing the EICs of internal standards in blank samples with those in QC samples. Additionally, the tightness of clustering of QC samples was assessed using principal component analysis, while data reproducibility was evaluated by calculating Pearson correlation coefficients between QC samples. The response stability of multiple isotopic internal standards throughout the analytical sequence was monitored, and the relative standard deviation (RSD) of their peak areas was calculated to evaluate overall data quality. Data Analysis The feature peaks detected in this study were initially processed using relative standard deviation-based denoising. Missing values were imputed with half of the minimum value, and data were normalized using an internal standard-based method. The resulting data matrix, comprising feature peak numbers, sample names, and normalized peak areas, was imported into SIMCA version 18.0.1 (Sartorius Stedim Data Analytics AB, Umea, Sweden) for multivariate statistical analysis. The data were scaled and logarithmically transformed to reduce noise and mitigate the influence of high variance among variables. Unsupervised principal component analysis (PCA) was subsequently performed to visualize sample distribution and grouping patterns. Outliers were identified and excluded based on the 95% confidence interval in the PCA score plot. To investigate intergroup differences and identify significantly altered metabolites, supervised orthogonal partial least squares-discriminant analysis (OPLS-DA) was employed. The model's explanatory power (R²) and predictive ability (Q²) were evaluated using 7-fold cross-validation. A permutation test with 200 iterations was further conducted to assess model robustness and to obtain intercept values for R² and Q². The Q² intercept value reflects the model's resistance to overfitting and its overall reliability, with lower values indicating better performance. Variables were ranked based on the variable importance in projection (VIP) score from the first predictive component of the OPLS-DA model. Metabolites with VIP > 1 and a p-value < 0.05 from Student’s t-test were considered statistically significant. Pathway enrichment analysis was subsequently performed using the KEGG and MetaboAnalyst databases. Results Metabolite Identification, Data Processing, and Intergroup Profiling Untargeted metabolomic analysis initially detected 43,513 feature peaks, as illustrated in Fig. 2 a. Following data preprocessing, 28,369 feature peaks were retained, among which 1,744 metabolites were confirmed with MS/MS secondary identification. The classification of these identified metabolites is presented in Fig. 2 b. After normalization, all samples were subjected to hierarchical clustering analysis, and a heatmap was generated (Fig. 2 c). Clear separation between the AT (aortic dissection postoperative) and HC (healthy control) groups was observed, indicating systematic differences in their metabolic profiles. Evaluation of Data Quality and Stability To ensure the reliability of the metabolomic data, systematic quality control was implemented. First, examination of the extracted ion chromatograms (EICs) of isotopic internal standards in the QC samples revealed highly consistent retention times, sharp and symmetric peak shapes, and minimal fluctuations in response intensity (Fig. 3 a, 3 b), indicating that the liquid chromatography-mass spectrometry (LC-MS) system remained stable throughout the entire sample analysis sequence. Meanwhile, comparison of the EICs of internal standards between blank samples and QC samples showed no detectable internal standard signals in the blanks, effectively ruling out potential system contamination (Fig. 3 c, 3 d). To further evaluate the overall quality of the metabolomics data, we systematically investigated the stability of the metabolic profiles across all samples using principal component analysis (PCA). The results demonstrated that all quality control (QC) samples exhibited highly clustered distribution in the PCA score plot (Fig. 4 a), indicating excellent stability of the LC-MS/MS analytical process and effective control of instrumental fluctuations and systematic errors. In striking contrast, the actual biological samples showed distinctly dispersed distribution, reflecting genuine intergroup biological differences. Further one-dimensional PCA-X distribution analysis of QC samples revealed that all quality control samples were distributed within ± 2 standard deviations along the first principal component, with no significant trend observed according to the injection order, further confirming the high stability of the analytical system (Fig. 4 b). Additionally, correlation analysis among QC samples showed Pearson correlation coefficients all greater than 0.93, demonstrating high reproducibility of metabolite quantification results (Fig. 4 c). Finally, we validated quantitative accuracy by examining the response stability of isotopic internal standards: all six internal standards exhibited excellent response stability throughout the analytical sequence, with relative standard deviations (RSD) of peak areas ranging from 1.35% to 16.75%. Notably, five of these internal standards showed RSD values below 5.4% (Table 1). These results collectively demonstrate the reliability and accuracy of our data from multiple perspectives, providing a solid foundation for subsequent analyses. Table 1. Response stability data of isotopic internal standards Analysis of Overall Metabolic Profile Characteristics Principal component analysis (PCA) revealed significant separation between the serum metabolic profiles of the aortic dissection postoperative (AT) group and the healthy control (HC) group (Fig. 5 a). The cumulative contribution rate of the first (PC1) and second (PC2) principal components was 64.1%, with PC1 accounting for 49.4% and PC2 for 14.7%. Samples from the AT group were predominantly distributed in the left side of the negative PC1 axis and the upper side of the positive PC2 axis, while HC group samples clustered in the right side of the positive PC1 axis and the lower side of the negative PC2 axis. The non-overlapping 95% confidence intervals between the two groups indicated significant alterations in metabolic profiles following surgery. To more reliably assess intergroup metabolite differences and classification correlations, orthogonal partial least squares-discriminant analysis (OPLS-DA) was employed. The results demonstrated clear separation between the AT and HC groups' metabolic profiles (Fig. 5 b). The first predictive component (t [ 1 ] P) of the model explained 35.5% of the variation, while the first orthogonal component (t [ 1 ] O) accounted for 15.4% of the variation, indicating the effectiveness of the OPLS-DA model in distinguishing the metabolic characteristics between the two groups. In the score plot, samples from the AT and HC groups showed distinct separation along the first predictive component axis with no overlapping distribution areas, further confirming significant postoperative changes in metabolic profiles. The reliability of the OPLS-DA model was confirmed through 200 permutation tests (Fig. 5 c–d). The model's explanatory power (R²Y) and predictive ability (Q²) reached 0.968 and 0.96, respectively. All permuted models exhibited significantly lower R²Y and Q²values compared to the original model, with the original parameters located at the extreme right of the random distribution (p < 0.05). None of the 200 permuted models outperformed the original model. Furthermore, the Q² intercept was − 1.45, substantially below the threshold of 0.05, indicating no overfitting in the model. These results collectively demonstrate that the OPLS-DA model robustly and significantly distinguishes the metabolic characteristics between postoperative aortic dissection patients and healthy individuals. Screening and Identification of Key Differential Metabolites Based on combined univariate (t-test, p 1) screening criteria, a total of 791 significantly differential metabolites were identified, including 416 upregulated and 375 downregulated metabolites in the postoperative (AT) group. As shown in the volcano plot (Fig. 6 a), the top 10 most significantly upregulated and downregulated metabolites (20 in total) were selected for annotation (Additional Table 2).The Z-score distribution plot of differential metabolites (Fig. 6 b) clearly displays the standardized abundance distribution of these 20 selected significant metabolites in the healthy control (HC) group and the aortic dissection postoperative (AT) group. As illustrated, the vast majority of metabolites exhibited distinctly opposite distribution patterns between the two groups. In the HC group, metabolites such as uridine, N-methylpropionamide, and phospholipid PC(18:4/20:3) showed Z-score values predominantly concentrated above the zero axis, indicating their abundances were higher than the average level across all samples. Conversely, in the AT group, these metabolites demonstrated significant shifts toward the negative side of the zero axis, suggesting substantially reduced abundances after surgery.In contrast, certain metabolites including 2-acetylthiazole and 2-methylbutyrylglycine, which already showed relatively low levels in the HC group (mean Z-score close to or less than zero), exhibited further distribution shifts toward the negative region in the AT group, indicating more pronounced downregulation trends. These visualization results were highly consistent with statistical analyses (VIP > 1, p < 0.05, and large absolute values of Log₂(Fold Change)), collectively confirming the extensive metabolic disturbances in patients following aortic dissection surgery. Hierarchical clustering analysis (using Euclidean distance matrix and complete linkage method) of the top 10 significantly upregulated and downregulated metabolites (20 in total) revealed distinct clustering patterns (Fig. 6 c). The metabolites were divided into two main clusters: Cluster A contained 10 metabolites including N-Methylpropionamide and 2-Acetylthiazole, while Cluster B comprised 10 metabolites including Uridine and PC(22:6(4Z,7Z,10Z,13Z,16Z,19Z)/22:6(4Z,7Z,10Z,13Z,16Z,19Z)). Sample grouping analysis demonstrated that healthy control (HC) samples predominantly distributed along the left branch of the heatmap, whereas postoperative (AT) samples clustered on the right branch. Regarding expression patterns, Cluster A metabolites exhibited consistently low expression intensity in the AT group, while Cluster B metabolites showed consistently high expression intensity in the AT group. Distribution Characteristics of Key Differential Metabolites Boxplot analysis (integrated and presented in Fig. 7 ) clearly revealed extremely significant intergroup differences in the concentrations of four key metabolites between the postoperative (AT) and healthy control (HC) groups (all p-values < 1×10⁻²⁰). Specifically, the median concentrations of all four metabolites (uridine, phospholipid PC(18:4/20:3), N-methylpropionamide, and 2-acetylthiazole) were significantly lower in the AT group compared to the HC group. Beyond the overall concentration reduction, each metabolite exhibited unique distribution characteristics: uridine showed a narrower distribution range (IQR) in the AT group; phospholipid PC(18:4/20:3) displayed more high-value outliers in the HC group; N-methylpropionamide exhibited right-skewed distribution (longer upper whisker) in the AT group; while 2-acetylthiazole showed similar IQR widths between groups but completely non-overlapping distribution areas (see Supplementary Materials for boxplots of remaining metabolites). Visualization of the Magnitude of Changes in Differential Metabolites The magnitude of changes in the top 10 significantly upregulated and downregulated metabolites (20 in total) was jointly analyzed using a needle plot (Fig. 8 a) and a radar chart (Fig. 8 b). The needle plot, with log₂ Fold Change as the x-axis and VIP value gradient as color depth, identified N-methylpropionamide (log₂FC = -3.66, VIP = 1.63) as the most downregulated metabolite, while the glutamine-threonine dipeptide (Gln-Thr, log₂FC = 4.59, VIP = 1.85) was the most upregulated metabolite. All metabolites exhibited *** level significance (p < 0.001). The downregulated group was predominantly distributed in the negative range (log₂FC: -1.72 to -3.66), while the upregulated group was concentrated in the positive range (log₂FC: 1.30 to 4.59). Further visualization via radar chart intuitively displayed the expression change patterns of the top 10 significantly upregulated and downregulated metabolites, represented by log₂(Fold Change). As shown in Fig. 8 b, all 20 metabolites reached extremely significant levels (p < 0.001). The trajectory of upregulated metabolites was largely located outside the peripheral grid line (log₂FC = 1), with the dipeptide Gln-Thr showing the most pronounced change (log₂FC = 4.59). In contrast, the trajectory of downregulated metabolites was concentrated in the central and inner regions, with N-methylpropionamide exhibiting the greatest degree of downregulation (log₂FC = -3.66). The needle and radar charts clearly reveal bidirectional and substantial concentration changes in serum metabolites following aortic dissection surgery, demonstrating distinct spatial distribution patterns between upregulated and downregulated metabolites in terms of the magnitude of change. Metabolite Correlation Interaction Network Integrated analysis based on Pearson correlation network (Fig. 9 a) and chord diagram (Fig. 9 b) revealed core features of the postoperative serum metabolite interaction network. The study found that the downregulated metabolite cluster (e.g., 2-ketobutyric acid, 6-hydroxynorleucine) exhibited significant intra-cluster synergistic effects, characterized by strong positive correlations (r > 0.8). Correspondingly, the upregulated metabolite cluster (e.g., uridine, LPA(20:4)) also showed significant positive correlations (e.g., r = 0.848 between uridine and LPA(20:4)). More importantly, strong negative correlations (r < -0.7) were widely observed between the two metabolite clusters. Among them, the most representative were the strong negative correlation between the most downregulated metabolite, N-methylpropionamide, and the most upregulated metabolite, glutamine-threonine dipeptide (r = -0.804), as well as the significant negative correlation between uridine and 2-acetylthiazole (r = -0.886). These relationships were further validated by chord diagram visualization. The results indicated significant intra-cluster synergy and inter-cluster antagonism among metabolites. Downregulated metabolites (e.g., uridine, N-methylpropionamide) formed tightly connected positive correlation clusters (mostly thick red chords), indicating their coordinated downregulation after surgery. In contrast, upregulated and downregulated metabolite clusters were generally connected by blue negative correlation chords, demonstrating systematic antagonistic relationships. For example, strong negative correlations were observed between the most downregulated metabolite, N-methylpropionamide, and certain upregulated metabolites. Furthermore, the diagram clearly illustrated the participation of different superclasses of metabolites in postoperative metabolic perturbations, with lipids and organic acids constituting the major nodes in the network. Analysis of Metabolic Pathway Perturbations: KEGG Pathway Enrichment Analysis To gain deeper insights into the functional characteristics and potential biological significance of the differential metabolites identified in the serum metabolomics data of postoperative aortic dissection patients, we performed a comprehensive bioinformatics analysis.. The KEGG classification analysis (Fig. 10 a) revealed that these metabolites were primarily enriched in pathways related to amino acid metabolism, carbohydrate metabolism, and membrane transport. The perturbation of these pathways was further quantified using Differential Abundance (DA) Score analysis (Fig. 10 b). This analysis delineated the direction and magnitude of changes within the enriched pathways. In amino acid metabolism, we observed a marked reduction in the abundance of D-amino acid metabolism (DA Score = -0.8) and glycine, serine, and threonine metabolism (DA Score = -0.4). Concurrently, energy metabolism pathways were significantly suppressed, as evidenced by the downregulation of 2-oxocarboxylic acid metabolism (DA Score = -0.43) and central carbon metabolism in cancer (DA Score = -0.86). Furthermore, pathways associated with membrane transport, such as ABC transporters (DA Score = -0.30), also showed decreased abundance. The enrichment bubble plot (Fig. 10 c) provided a consolidated view of both the statistical significance and the magnitude of these pathway alterations. This analysis validated the above findings, confirming that ABC transporters (enrichment factor = 0.167, p = 1.13×10⁻¹³) and aminoacyl-tRNA biosynthesis (enrichment factor = 0.269, p = 1.22×10⁻¹¹) were among the most significantly perturbed pathways. Key amino acid metabolism pathways, including D-amino acid metabolism (p = 5.99×10⁻⁶) and glycine, serine, and threonine metabolism (p = 1.79×10⁻⁷), as well as energy-related pathways like 2-oxocarboxylic acid metabolism (p = 1.00×10⁻⁵), were all robustly confirmed. Collectively, the results from these complementary analyses demonstrate that aortic dissection surgery induces extensive reprogramming of amino acid metabolism, energy homeostasis, and membrane transport processes. Identification of Key Perturbed Pathways through Enrichment and Topological Analysis To further identify core pathways with both statistical significance and biological impact from these enriched pathways, topological analysis based on p-value and impact value was subsequently performed. This analysis helps identify pathways that occupy key positions within the overall metabolic network. First, the differential metabolites were matched against the KEGG and PubChem databases (Supplementary Table 2), followed by metabolic pathway analysis based on the human pathway database. Pathways with the greatest statistical significance and biological impact were screened by calculating the enrichment degree (p-value) and topological impact value (Impact) (Supplementary Table 3). Significance analysis revealed that the differential metabolites were significantly enriched in multiple core metabolic pathways (Fig. 11 a). Among them, the aminoacyl-tRNA biosynthesis pathway (p = 1.02×10⁻⁴, Impact = 0.225) contained 13 differential metabolites, including glycine (C00037) and L-glutamine (C00064). The glycine, serine, and threonine metabolism pathway (p = 6.93×10⁻⁴, Impact = 0.380) involved 9 metabolites; the nitrogen metabolism pathway (p = 7.42×10⁻⁴, Impact = 0.001) contained 8 metabolites; and the arginine and proline metabolism pathway (p = 1.93×10⁻³, Impact = 0.203) involved 11 metabolites. Topological analysis (Fig. 11 b) further revealed high-impact metabolic pathways: the alanine, aspartate, and glutamate metabolism pathway (Impact = 0.649) and the taurine and hypotaurine metabolism pathway (Impact = 0.433). Additionally, the pantothenate and CoA biosynthesis pathway (p = 0.012, Impact = 0.038) and the pyruvate metabolism pathway (p = 0.017, Impact = 0.240) also showed significant alterations. Notably, sphingosine (C00319) in sphingolipid and fatty acid metabolism pathways, palmitoylcarnitine (C02990), and indolelactic acid (C02043) in the tryptophan metabolism pathway were significantly altered. Integrated Network Enrichment Analysis Reveals Global Characteristics of the Postoperative Metabolic Regulatory Network Network Enrichment Analysis Based on KEGG Database Reveals Global Characteristics of the Metabolic Regulatory Network Following Aortic Dissection Surgery (Fig. 12 ). This analysis integrated multi-level information including metabolic pathways, modules, enzymes, reactions, and metabolites to construct a comprehensive metabolic interaction network. The results demonstrated significant enrichment features (p < 1×10⁻⁵) in multiple key metabolic pathways, including taurine and hypotaurine metabolism (hsa00430, p = 1.54×10⁻⁵), ABC transporters (hsa02010, p = 8.60×10⁻⁶), sphingolipid signaling pathway (hsa04071, p = 4.99×10⁻⁵), mTOR signaling pathway (hsa04150, p = 1×10⁻⁶), and apoptosis (hsa04210, p = 1×10⁻⁶). Core metabolic nodes in the network involved amino acid metabolism-related compounds (e.g., glycine C00037, L-alanine C00041, and L-aspartate C00049), lipid metabolism-related molecules (e.g., sphingosine C00319, sphingomyelin C00550, and 1-acyl-sn-glycero-3-phosphocholine C04230), as well as energy metabolism intermediates (e.g., taurine C00245 and hypotaurine C00519). Key enzyme nodes primarily included sphingolipid metabolism-related enzymes (e.g., sphingosine kinase EC 2.7.1.91 and sphingomyelin synthase EC 2.7.8.27), amino acid metabolism enzymes (e.g., glycine amidinotransferase EC 2.1.4.1 and L-lactate dehydrogenase EC 1.1.1.27), and energy metabolism enzymes (e.g., xanthine dehydrogenase EC 1.17.1.4 and Na⁺/K⁺-ATPase EC 7.2.2.13). This network analysis clearly illustrates the distribution characteristics and interrelationships of differential metabolites within metabolic pathways, providing a systems-level perspective for understanding postoperative metabolic disturbances. Differential Metabolites Demonstrate Excellent Diagnostic Value Based on ROC Curve Analysis Evaluation of the diagnostic efficacy of differential metabolites through ROC curve analysis revealed that multiple metabolites exhibited outstanding classification performance in distinguishing postoperative aortic dissection patients (AT group) from healthy controls (HC group) (Supplementary materials). Among them, uridine, phosphatidylcholine PC(18:4/20:3), N-methylpropionamide, and 2-acetylthiazole all achieved AUC values of 1.0 (95% CI: 1.0–1.0), indicating perfect discriminatory ability in the training set. Additionally, metabolites such as oxamate (AUC = 1.0) and 3-amino-4-hydroxyphenyl sulfone (AUC = 1.0) also demonstrated exceptionally high diagnostic potential. Further analysis showed that these metabolites exhibited excellent specificity and sensitivity. For example, uridine at a threshold of 0.18 achieved a specificity of 96.7% and a sensitivity of 100%, while PC(18:4/20:3) at a threshold of 0.13 showed a specificity of 100% and a sensitivity of 86.7%. These results suggest that these metabolites may serve as potential biomarkers for diagnosis or monitoring following aortic dissection surgery. Discussion Metabolomics, as a major branch of systems biology, provides a powerful tool for elucidating the metabolic basis of disease occurrence and progression by systematically analyzing the global changes of small-molecule metabolites within organisms. In recent years, with the rapid advancement of metabolomic technologies, its application in cardiovascular disease research has become increasingly widespread. This technology not only aids in identifying metabolic biomarkers associated with diseases but also reveals potential metabolic pathway abnormalities, thereby offering new perspectives and methods for the diagnosis, prognostic assessment, and treatment strategies of cardiovascular diseases [ 6 , 7 ]. This study employed untargeted metabolomics technology to conduct, for the first time, a comprehensive and systematic comparison of serum metabolic profiles between postoperative patients with acute DeBakey type I aortic dissection and a healthy population, revealing characteristic postoperative metabolic reprogramming patterns. The results showed significant differences in serum metabolic profiles between postoperative patients and the healthy control group. Through multivariate statistical analysis, a total of 791 significantly differential metabolites were identified, with 416 upregulated and 375 downregulated, indicating that patients undergo substantial metabolic remodeling after aortic dissection surgery. This finding is consistent with multiple studies. Macrophage metabolic reprogramming plays a key role in the progression of aortic dissection, particularly by promoting vascular inflammation, extracellular matrix degradation, and elastic lamina fragmentation through the HIF-1α-ADAM17 pathway, thereby exacerbating the condition [ 11 ]. Furthermore, multi-omics studies have shown that FABP5 + macrophages differentiate into a pro-inflammatory phenotype upon stimulation by metabolic substrates, releasing large quantities of cytokines that further drive the pathological process of aortic dissection [ 12 ]. These mechanisms collectively support the notion of intense metabolic alterations following surgery. Pathway analysis further highlighted the central role of the aminoacyl-tRNA biosynthesis pathway. As a critical hub connecting metabolism and protein translation, this pathway is not only responsible for the correct coupling of amino acids to their cognate tRNAs, ensuring translational fidelity, but is also extensively involved in processes linking cellular metabolism and translational control [ 13 ]. Dysregulation of aminoacyl-tRNA synthetase function may impact the rate and accuracy of protein synthesis, thereby interfering with physiological processes such as postoperative tissue repair and immune responses [ 14 , 15 ]. Concurrently, the significant enrichment of amino acid metabolic pathways—including glycine, serine, and threonine metabolism; arginine and proline metabolism; and D-amino acid metabolism—suggests that these pathways play important roles in disease progression. Studies have shown that the plasma amino acid profiles of aortic dissection (AD) patients differ significantly from those with coronary heart disease (CHD), with notable changes in levels of amino acids such as glycine, serine, and proline, particularly in acute AD [ 16 ]. This indicates that the body is in a state of hypercatabolism post-surgery, mobilizing amino acids in large quantities for energy production, acute-phase protein synthesis, and tissue repair. Following cardiac surgery, especially with cardiopulmonary bypass, protein catabolism is enhanced, and the degradation of amino acids such as valine, leucine, and isoleucine is exacerbated, which may be associated with postoperative complications like acute kidney injury [ 17 ]. Topological analysis further identified several high-impact core pathways, among which the alterations in taurine and hypotaurine metabolism are particularly noteworthy. These amino acid derivatives possess antioxidant and membrane-stabilizing functions, and their metabolic disturbances are likely closely related to intraoperative ischemia-reperfusion injury. Research indicates that taurine can mitigate ischemia-reperfusion injury by stabilizing cell membranes and scavenging free radicals [ 18 ]. The postoperative changes in taurine and hypotaurine levels may reflect the body's adaptive response to oxidative stress. Taurine levels are significantly elevated in models of hepatic ischemia-reperfusion [ 19 ], and hypotaurine, as its precursor, may exert protective effects through similar mechanisms. Metabolomic studies have already identified taurine as a differential metabolite in the serum of aortic dissection patients [ 20 ], further supporting its potential value in postoperative metabolic regulation. These pathway perturbations reflect specific pathophysiological alterations: The significant downregulation of energy metabolism-related metabolites such as uridine, along with changes in multiple key intermediates of the tricarboxylic acid (TCA) cycle and 2-oxocarboxylic acid metabolism, suggests impaired mitochondrial energy production and severe dysregulation of the body's energy metabolism. Uridine, as a nucleotide precursor, participates in UTP/ATP synthesis and glycogen metabolism [ 21 , 22 ]; its downregulation may lead to insufficient energy supply, adversely affecting postoperative recovery [ 23 ]. Similar phenomena have been reported in other cardiovascular diseases. For instance, maladaptive right ventricular remodeling in pulmonary hypertension is associated with disturbances in TCA cycle intermediates [ 24 ]. The current results provide further evidence that postoperative energy reprogramming in aortic dissection is linked to antioxidant pathways, as suggested in our earlier work [ 25 ]. abnormal TCA cycle and amino acid metabolism are also observed in abdominal aortic aneurysms [ 26 ]. These consistent findings suggest that mitochondrial dysfunction may be a common pathological basis for cardiovascular diseases.Secondly, the significant enrichment of various amino acid metabolic pathways (such as glycine, serine, and threonine metabolism, and branched-chain amino acid metabolism) collectively confirms that the body is in a state of hypercatabolism post-surgery. In this state, amino acids are extensively mobilized, being consumed as an energy source on one hand, and utilized for the synthesis of acute-phase proteins and tissue repair processes on the other. This finding is highly consistent with the altered protein metabolism observed in patients following cardiac surgery, particularly those who have undergone cardiopulmonary bypass [ 17 ]. Furthermore, the significant alterations in phosphatidylcholine and sphingolipid metabolism may reflect surgery-induced erythrocyte destruction, vascular endothelial injury, or compromised mitochondrial membrane integrity. The observed downregulation of phosphatidylcholines (e.g., PC(18:4/20:3)) and various sphingolipids in this study aligns with previous research: these membrane lipid components are often significantly reduced in the serum of patients with acute aortic dissection [ 27 ]. Sphingolipid metabolism not only plays a crucial role in the post-myocardial infarction repair phase [ 28 ] but is also persistently dysregulated in the progression of cardiovascular diseases like atherosclerosis [ 29 ], underscoring the core importance of these metabolites in cardiovascular pathophysiology. Particularly noteworthy is that the downregulation of the ABC transporter pathway may have multifaceted and profound impacts on postoperative metabolic homeostasis. This pathway acts as a "gatekeeper" in the transmembrane transport of lipids, drugs, toxins, and various metabolites [ 30 – 34 ]. Its functional inhibition could lead to multiple consequences: firstly, it may affect lipid metabolism (e.g., reverse cholesterol transport), exacerbating dyslipidemia [ 31 , 32 ]; secondly, it could impede the timely efflux of intracellular metabolic waste products, leading to their accumulation and potentially inducing damage such as oxidative stress; thirdly, it may alter drug distribution and metabolism, affecting drug efficacy and increasing the risk of adverse reactions [ 30 ]. Therefore, the downregulation of ABC transporters may represent a potential key link connecting postoperative metabolic disturbances to clinical complications (e.g., altered drug sensitivity, toxin accumulation). Further correlation network analysis revealed intricate regulatory relationships among the metabolites. The differential metabolites displayed distinct co-expression patterns: strong positive correlations (r > 0.8) were observed within the downregulated metabolite cluster (e.g., between 2-ketobutyric acid and 6-hydroxynorleucine), while the upregulated metabolites (e.g., uridine and LPA(20:4)) also exhibited high internal synergy (r = 0.848). More importantly, strong antagonistic interactions (r < -0.7) were prevalent between the upregulated and downregulated metabolite clusters. Significant negative correlations were identified, for instance, between N-methylpropionamide and the glutamine-threonine dipeptide (r = -0.804), and between uridine and 2-acetylthiazole (r = -0.886). This highly organized metabolic network reprogramming indicates that the postoperative metabolic alterations constitute a systematic biological process. Metabolites interact and co-regulate each other through a sophisticated network, collectively defining the overall metabolic disturbance profile following surgery. This study also identified a panel of metabolites with potential clinical value as biomarkers. Metabolites such as uridine, phosphatidylcholine PC(18:4/20:3), N-methylpropionamide, and 2-acetylthiazole demonstrated exceptional discriminatory power (AUC = 1.0), enabling accurate differentiation between postoperative patients and healthy individuals. These findings offer novel molecular targets for postoperative metabolic monitoring. Conclusion In summary, this metabolomic investigation delineates a profound metabolic upheaval in patients following surgical repair of acute aortic dissection. The identified reprogramming, characterized by coherent perturbations in pathways critical for protein synthesis, energy homeostasis, and membrane transport, underscores a systemic biological response to major cardiovascular surgery. The robust discriminatory capacity of the discovered metabolic signature not only offers promising biomarkers for postoperative assessment but, more importantly, provides a metabolic framework for understanding the pathophysiology of recovery. These insights pave the way for future research aimed at determining whether modulating these metabolic pathways can positively influence clinical outcomes. Limitations This study has several limitations. First, as a single-center observational study with a limited sample size, the findings require further validation in larger-scale, multi-center prospective cohorts in the future. Second, while the study revealed associations between metabolites and pathways, the causal biological mechanisms have not been elucidated through functional experiments. Finally, the relationship between these metabolic markers and long-term clinical outcomes in patients warrants further exploration. Declarations Availability of Data and Materials The metabolomics dataset generated and analyzed during the current study is not publicly available due to patient privacy and ethical restrictions but is available from the corresponding author on reasonable request. The data supporting the findings of this study are included within the article and its supplementary materials. All materials and protocols used in this study are described in detail in the 'Materials and Methods' section. Clinical samples were used under the approval of the Medical Ethics Committee of the First Affiliated Hospital of University of South China. Author Contributions Yuji Xiao designed the study, performed the LC-MS-based metabolomic experiments, conducted data analysis, and drafted the manuscript. Jia Liu and Wanru Ma contributed equally to clinical data collection and sample management from the First Affiliated Hospital cohort. Haonan Zhang and Heng Yang optimized metabolite extraction protocols and conducted multivariate statistical analyses. Juan Wu performed statistical validation. Jun Tang provided valuable clinical insights and contributed to the discussion of the results. Yucai Huang participated in data curation. Yaoguang Feng provided essential clinical resources and oversight. Corresponding author Zhengwen Lei conceived the project, secured funding, provided overall supervision, and revised the manuscript critically for important intellectual content. All authors reviewed and approved the final manuscript. Ethics Approval and Consent to Participate Ethics Approval and Consent to Participate: This study was approved by the Medical Ethics Committee of the First Affiliated Hospital of University of South China (Approval No: 2024LL1016001). Written informed consent was obtained from all participants or their legal guardians prior to enrollment. Acknowledgments This study was supported by colleagues from the Department of Thoracic and Cardiovascular Surgery, Health Management Center, and Medical Records Room of the First Affiliated Hospital of University of South China. We sincerely appreciate Funding This work was supported by grant from Hunan Provincial Natural Science Foundation (2023JJ50152) and Hengyang City Science and Technology Innovation Plan (Hengke Zi [2023] No. 14). Conflict of Interest The authors declare no conflict of interest. References Chandiramani A, Al-Tawil M, Elleithy A, et al. Organ-specific malperfusion in acute type A aortic dissection: epidemiological meta-analysis of incidence rates[J]. BJS open, 2025, 9(1): zrae146. Yamashita Y, Joo K, Okamoto K, et al. Postoperative Maximal Aortic Diameter is a Significant Predictor of Dilation of the Residual Dissected Aorta after Aortic Replacement for Acute Debakey Type I Aortic Dissection[J]. Annals of Vascular Surgery, 2022, 81: 121-128. 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Frontiers in Pharmacology, 2024, 15: 1423416. Additional Declarations No competing interests reported. Supplementary Files Pyrogallol.jpg TACROLIMUS.jpg Pyruvaldehyde.jpg Uridine.jpg Oxamate.jpg Idoxanthin.jpg NMethylpropionamide.jpg 2Acetylthiazole.jpg PC1846Z9Z12Z15Z2038Z11Z14Z.jpg 5Amino1pentanol.jpg 3Amino4hydroxyphenylsulfone.jpg 2Methylbutyrylglycine.jpg NAcetylvaline.jpg 3METHYLGLUTACONICACID.jpg PS1839Z12Z15Z1829Z12Z.jpg S4Fluorophenylmercapturicacid.jpg 1HIndole5sulfonamide23dihydroNNdimethyl2oxo34567tetrahydro1Hindol2ylmethylene.jpg PC2264Z7Z10Z13Z16Z19Z2264Z7Z10Z13Z16Z19Z.jpg Phenol2435dichlorophenylamino6methyl2pyrimidinyl.jpg 345trihydroxy6345trihydroxybenzoyloxyoxan2ylmethyl345trihydroxybenzoate.jpg 5Amino1pentanol.jpg 3METHYLGLUTACONICACID.jpg Idoxanthin.jpg NMethylpropionamide.jpg Phenol2435dichlorophenylamino6methyl2pyrimidinyl.jpg PC1846Z9Z12Z15Z2038Z11Z14Z.jpg PS1839Z12Z15Z1829Z12Z.jpg Pyrogallol.jpg PC2264Z7Z10Z13Z16Z19Z2264Z7Z10Z13Z16Z19Z.jpg Oxamate.jpg Pyruvaldehyde.jpg NAcetylvaline.jpg S4Fluorophenylmercapturicacid.jpg TACROLIMUS.jpg 1HIndole5sulfonamide23dihydroNNdimethyl2oxo34567tetrahydro1Hindol2ylmethylene.jpg Uridine.jpg 345trihydroxy6345trihydroxybenzoyloxyoxan2ylmethyl345trihydroxybenzoate.jpg 2Acetylthiazole.jpg 3Amino4hydroxyphenylsulfone.jpg 2Methylbutyrylglycine.jpg 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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09:54:51","extension":"xml","order_by":69,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":132786,"visible":true,"origin":"","legend":"","description":"","filename":"74064e6d979d42bca756f7c5ff2a2cbb1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7708816/v1/c14858af91626817840a87d5.xml"},{"id":96246220,"identity":"a2af7243-fa87-4eff-964d-704f6ca1efd0","added_by":"auto","created_at":"2025-11-19 07:25:05","extension":"html","order_by":70,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":157003,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7708816/v1/d5b93b0de55e33e22e00c0b7.html"},{"id":96071134,"identity":"a2fce926-973e-4c5b-9e74-3358602ceca4","added_by":"auto","created_at":"2025-11-17 09:54:39","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":102206,"visible":true,"origin":"","legend":"\u003cp\u003eWorkflow of the untargeted metabolomics study.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7708816/v1/cf3737e9dc5ca0c1a29df5a5.png"},{"id":96071125,"identity":"088209af-33f0-4159-920e-c256163737f6","added_by":"auto","created_at":"2025-11-17 09:54:38","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":346354,"visible":true,"origin":"","legend":"\u003cp\u003eMetabolite identification results and overall distribution characteristics. (a) Total ion chromatogram (TIC) of raw data; (b) Donut chart of metabolite classification; (c) Heatmap of hierarchical clustering analysis for all samples: The x-axis represents different sample groups, the y-axis represents all metabolites, and the color in each cell indicates the relative expression level of the corresponding metabolite—red denotes high expression, while blue indicates low expression.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7708816/v1/6d12f9f524bfe699693eae05.png"},{"id":96071184,"identity":"1c5f11e0-1ef1-42ab-aa2c-bfd938ce499e","added_by":"auto","created_at":"2025-11-17 09:54:41","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":109049,"visible":true,"origin":"","legend":"\u003cp\u003eEvaluation of LC-MS system stability and quality control. (a) EIC chromatograms of internal standards in positive ion mode from QC samples; (b) EIC chromatograms of internal standards in negative ion mode from QC samples: The x-axis represents retention time (minutes), and the y-axis indicates relative response intensity. The highly overlapped chromatographic peaks from 10 injections demonstrate consistent retention times and peak shapes, indicating stable chromatographic separation conditions and consistent ionization efficiency throughout the analytical process. (c) Comparison of EIC chromatograms of internal standards in positive ion mode between blank and QC samples; (d) Comparison of EIC chromatograms of internal standards in negative ion mode between blank and QC samples: EIC chromatograms of a specific internal standard in blank samples (black line, n=6) and QC samples (red line, n=10) are shown. QC samples exhibit excellent chromatographic peak reproducibility, while no significant peak signals are observed at corresponding retention times in blank samples, indicating no cross-contamination during the analytical process.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7708816/v1/10c84f92b6071a5d69b29cc4.png"},{"id":96071250,"identity":"9807f03e-a0df-427c-8478-f868b431be96","added_by":"auto","created_at":"2025-11-17 09:54:45","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":150039,"visible":true,"origin":"","legend":"\u003cp\u003eMultivariate statistical analysis for data quality control.(a) Principal component analysis (PCA) score plot showing the distribution of samples in the principal component space. Green dots represent quality control (QC) samples, and blue dots represent experimental samples. The X-axis and Y-axis correspond to the first principal component (PC1) and the second principal component (PC2), respectively.(b) One-dimensional PCA-X distribution plot of QC samples. The X-axis displays the PC1 scores, and the Y-axis represents the frequency density of the samples.(c) Heatmap of correlation analysis among QC samples. The color gradient reflects Pearson correlation coefficients, with darker colors indicating stronger positive correlations.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7708816/v1/b15d0ff72c21be823381e782.png"},{"id":96071247,"identity":"6d7eb280-6b66-448c-86a9-d73974ab8742","added_by":"auto","created_at":"2025-11-17 09:54:45","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":136862,"visible":true,"origin":"","legend":"\u003cp\u003eValidation of intergroup metabolic differences using PCA and OPLS-DA models. (a) PCA score scatter plot: The x-axis represents the first principal component (PC1, 49.4% variance contribution), and the y-axis represents the second principal component (PC2, 14.7% variance contribution). Each point represents a sample, with identical colors and shapes corresponding to the same group. The spatial distance between sample points reflects the similarity of their metabolic composition. (b) OPLS-DA score plot: The x-axis represents the first predictive component t[1]P (explaining 35.5% of intergroup variation), and the y-axis represents the first orthogonal component t[1]O (explaining 15.4% of intragroup variation). AT and HC group samples are distinguished by color and shape. (c) Frequency distribution of OPLS-DA permutation test: The x-axis represents parameter values of permuted models (Q² left, R²Y right), and the y-axis represents the corresponding frequency. The red histogram shows the distribution of Q² values from random permuted models, while the blue histogram shows the distribution of R²Y values. The dashed line indicates the position of the original model parameters. (d) Regression analysis of OPLS-DA permutation test: The x-axis represents permutation retention (1.0 indicates the original model), and the y-axis represents R²Y (blue circles) and Q² (red squares) values. The dashed lines represent the regression lines of the permuted models, with R²Y and Q² intercepts of -0.14 and -1.45, respectively.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7708816/v1/bba934580349da5dc18be585.png"},{"id":96071175,"identity":"bdef74ca-63b0-40e6-b698-89282840c12e","added_by":"auto","created_at":"2025-11-17 09:54:41","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":351322,"visible":true,"origin":"","legend":"\u003cp\u003eAnalysis of differential metabolite screening and expression patterns. (a) Volcano plot of differential metabolites. The x-axis represents the log₂ fold change of metabolite abundance, and the y-axis represents the negative logarithm of the p-value (-log₁₀P). According to the screening criteria (p-value \u0026lt; 0.05 and VIP \u0026gt; 1), red dots represent significantly upregulated metabolites (416), blue dots represent significantly downregulated metabolites (375), and gray dots indicate metabolites with no significant differences. The horizontal dashed line indicates the significance threshold (p = 0.05), and the vertical dashed line corresponds to zero fold change. (b) Z-score clustering plot of metabolite abundance. The x-axis represents the Z-value, and the y-axis represents the differential metabolites. Points of different colors represent samples from different groups. The formula used is: z = (x - μ)/σ, where x is the individual value, μ is the mean, and σ is the standard deviation. This plot visually compares the distribution of each metabolite across different groups and their deviation from the overall mean. (c) Hierarchical clustering analysis of differential metabolites. Rows represent metabolites, and columns represent samples. Colors reflect the relative abundance of metabolites (red: high expression; blue: low expression). Sample clustering demonstrates clear separation between the metabolic profiles of the HC and AT groups.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-7708816/v1/a7c8ed249baa6b3ca10b0c72.png"},{"id":96249346,"identity":"3cca035d-26df-4736-8c16-537447158f79","added_by":"auto","created_at":"2025-11-19 07:33:07","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":60851,"visible":true,"origin":"","legend":"\u003cp\u003eBox plots showing the concentration distributions of four key differential metabolites in the HC and AT groups. (a) Uridine, (b) 2-Acetylthiazole, (c) N-Methylpropionamide, (d) Phosphatidylcholine (PC(18:4(6Z,9Z,12Z,15Z)/20:3(8Z,11Z,14Z))). The y-axis represents the normalized concentration or quantitative value of each metabolite, and the x-axis represents the different sample groups.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-7708816/v1/9069ce29eb6b09d590de0d8e.png"},{"id":96071123,"identity":"a7449713-19b8-493c-a8ca-9b855f21fd22","added_by":"auto","created_at":"2025-11-17 09:54:38","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":189696,"visible":true,"origin":"","legend":"\u003cp\u003eAnalysis of change magnitude of differential metabolites. (a) Needle plot: Shows change magnitude (Log₂FC) and model importance (VIP value). Line length/direction indicates change magnitude/direction (left: downregulation; right: upregulation); point color indicates direction (blue: down; red: up); point size indicates VIP value. All metabolites: p \u0026lt; 0.001. (b) Radar chart: Rays represent metabolites; grid lines indicate log₂FC values. Vertex position indicates change magnitude (outer: upregulation; inner: downregulation).\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-7708816/v1/723779ff602c671ad7b23824.png"},{"id":96071214,"identity":"ab52ab79-c78b-4533-ace7-623da54a14ae","added_by":"auto","created_at":"2025-11-17 09:54:43","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":245331,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation network and functional interaction analysis of differential metabolites. (a) Correlation heatmap of significantly differential metabolites. The heatmap displays pairwise correlation coefficients among the identified differential metabolites. Color intensity indicates correlation strength, with red and blue representing positive and negative correlations, respectively. (b) Chord diagram illustrating multiple attributes and interaction relationships of differential metabolites. Each node represents a metabolite, with its area proportional to the magnitude of expression change (|Log₂(Fold Change)|) and its color indicating the KEGG pathway superclass. Connecting chords represent pairwise correlations between metabolites, with chord color indicating correlation direction (red: positive; blue: negative) and chord width proportional to the absolute correlation coefficient (|r|). The diagram comprehensively reveals the reconstructed characteristics of metabolites in terms of change magnitude, functional classification, and interaction patterns following aortic dissection surgery.\u003c/p\u003e","description":"","filename":"9.png","url":"https://assets-eu.researchsquare.com/files/rs-7708816/v1/ed97a550f792e3143d8a5758.png"},{"id":96249272,"identity":"fd36bd33-39cb-4d14-a367-3ce020e06f12","added_by":"auto","created_at":"2025-11-19 07:32:50","extension":"png","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":120524,"visible":true,"origin":"","legend":"\u003cp\u003eComprehensive analysis of KEGG pathway enrichment and perturbation. (a) KEGG pathway enrichment classification of differential metabolites. The y-axis shows the names of enriched KEGG metabolic pathways, and the x-axis shows the percentage of differential metabolites annotated to each pathway relative to the total number of annotated differential metabolites. (b) KEGG pathway enrichment and perturbation analysis based on differential metabolites. The y-axis shows the names of enriched KEGG metabolic pathways, and the x-axis shows the Differential Abundance (DA) Score. The length of the line segments represents the absolute value of the DA Score, and the size of the dots represents the number of differential metabolites annotated to the corresponding pathway. (c) KEGG enrichment plot of differential metabolites. The x-axis represents the Rich Factor for each pathway, and the y-axis shows the names of the KEGG metabolic pathways. The size of the dots represents the number of differential metabolites enriched in the pathway. The color indicates the p-value, with a redder color representing a smaller p-value and thus a more significant enrichment.\u003c/p\u003e","description":"","filename":"10.png","url":"https://assets-eu.researchsquare.com/files/rs-7708816/v1/1ef96d66aa24350e8311dafb.png"},{"id":96246129,"identity":"39900f54-9390-40e4-bc23-bf815b8126d0","added_by":"auto","created_at":"2025-11-19 07:24:44","extension":"png","order_by":11,"title":"Figure 11","display":"","copyAsset":false,"role":"figure","size":255218,"visible":true,"origin":"","legend":"\u003cp\u003eKEGG pathway enrichment and topological characteristics of differential metabolites. (a) Bubble plot of KEGG pathway enrichment analysis for differential metabolites. Each bubble represents a metabolic pathway. The vertical axis indicates the significance level of the enrichment analysis, represented by the negative natural logarithm of the enrichment p-value; a higher value or darker color denotes greater enrichment significance of the pathway. The horizontal axis represents the impact factor of the pathway in the topological analysis, with a higher value indicating greater importance of the pathway within the metabolic network. The bubble size is proportional to the impact factor value; larger bubbles indicate a higher impact factor for the pathway. (b) Treemap of KEGG pathway enrichment analysis for differential metabolites. Each rectangular block represents a metabolic pathway. The block size indicates the impact factor value of the pathway in the topological analysis; a larger area denotes higher importance of the pathway within the metabolic network. The block color represents the significance level of the enrichment analysis, indicated by the negative natural logarithm of the enrichment p-value; a darker color signifies more significant enrichment of the pathway.\u003c/p\u003e","description":"","filename":"11.png","url":"https://assets-eu.researchsquare.com/files/rs-7708816/v1/3597a09e219cd8a03c0b2cb9.png"},{"id":96246833,"identity":"c1209cab-16bf-4839-81b1-ec2fb755f113","added_by":"auto","created_at":"2025-11-19 07:26:44","extension":"png","order_by":12,"title":"Figure 12","display":"","copyAsset":false,"role":"figure","size":496710,"visible":true,"origin":"","legend":"\u003cp\u003eInteraction network of differential metabolites and pathways. Nodes in the network represent different entities: differential metabolites identified in this analysis are represented by green squares; KEGG metabolic pathways are denoted by red circles; chemical reactions are indicated by blue circles; enzymes are represented by yellow circles; molecular modules are shown as purple circles; metabolic background substances are depicted as green circles. Edges represent interaction relationships between entities.\u003c/p\u003e","description":"","filename":"12.png","url":"https://assets-eu.researchsquare.com/files/rs-7708816/v1/e142f1d209a9690aeed2bd40.png"},{"id":100356805,"identity":"6c5f8472-07d5-48c7-ab28-67d79952b01d","added_by":"auto","created_at":"2026-01-16 07:17:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3169702,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7708816/v1/f0957ab1-ab99-4b87-ba00-9fa22eebc0cb.pdf"},{"id":96246204,"identity":"5628fcf6-55ad-454e-982c-389a0e6232a2","added_by":"auto","created_at":"2025-11-19 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09:54:41","extension":"jpg","order_by":38,"title":"","display":"","copyAsset":false,"role":"supplement","size":1448568,"visible":true,"origin":"","legend":"","description":"","filename":"3Amino4hydroxyphenylsulfone.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7708816/v1/19e8ca4e9ca716163fdabcd5.jpg"},{"id":96071190,"identity":"25cdf3d2-cdbb-4d10-a0c9-acb0041a53c9","added_by":"auto","created_at":"2025-11-17 09:54:41","extension":"jpg","order_by":39,"title":"","display":"","copyAsset":false,"role":"supplement","size":1486821,"visible":true,"origin":"","legend":"","description":"","filename":"2Methylbutyrylglycine.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7708816/v1/051d735ab744aed6181d16eb.jpg"}],"financialInterests":"No competing interests reported.","formattedTitle":"Serum Metabolomics Reveals Metabolic Reprofiling and Perturbed Pathways after Aortic Dissection Surgery","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAortic dissection is a critical cardiovascular condition characterized by sudden onset and rapid progression. Particularly in acute DeBakey type I dissection, mortality increases by 1\u0026ndash;2% per hour [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Modern surgical techniques, such as Sun\u0026rsquo;s procedure and deep hypothermic circulatory arrest, represent the most effective treatment strategies currently available. However, the extensive surgical trauma and prolonged cardiopulmonary bypass often induce severe metabolic disturbances in patients postoperatively, significantly impacting clinical outcomes [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Nevertheless, systematic research on metabolic alterations following aortic dissection surgery remains exceedingly limited. The metabolic regulatory mechanisms underlying vascular repair have yet to be elucidated, and there is a notable clinical absence of efficient, specific biomarkers for the precise assessment and intervention of postoperative metabolic status [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. These gaps considerably constrain the optimization of postoperative management strategies and the improvement of long-term quality of life for patients. Metabolomics, a major branch of systems biology, provides a comprehensive reflection of the dynamic changes of small-molecule metabolites within organisms, offering a powerful tool for investigating disease mechanisms and discovering biomarkers. In recent years, metabolomics has demonstrated broad application prospects in the field of cardiovascular diseases, such as elucidating metabolic features in heart failure and ischemic heart disease [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Nevertheless, research on metabolic reprogramming in patients following aortic dissection surgery remains in its infancy, particularly regarding the mechanisms by which surgical stress perturbs metabolic networks. Furthermore, the association between postoperative metabolic disturbances and clinical outcomes\u0026mdash;such as organ function recovery and the occurrence of complications \u0026mdash; has yet to be thoroughly explored.\u003c/p\u003e\u003cp\u003eTherefore, elucidating the mechanisms of vascular repair from the perspective of metabolic regulation and developing targeted therapeutic strategies represent critical breakthroughs for improving patient prognosis [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], holding significant clinical importance for long-term outcomes. To address this research gap, we applied untargeted metabolomics to systematically analyze the serum metabolic profiles of patients following surgery for acute DeBakey type I aortic dissection compared with healthy controls. Our study aims not only to identify potential biomarkers that accurately reflect postoperative metabolic status but, more importantly, to uncover key pathways and network interaction mechanisms underlying postoperative metabolic disturbances. The findings of this research are expected to provide novel insights into postoperative metabolic stress and establish a theoretical foundation for developing targeted metabolic interventions to improve patient outcomes.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eData Collection\u003c/h2\u003e\u003cp\u003eSerum samples were collected from 30 postoperative patients with acute DeBakey type I aortic dissection who were admitted to the Department of Cardiothoracic and Vascular Surgery at the First Affiliated Hospital of University of South China between July and December 2024, along with 30 healthy controls recruited during the same period. All samples were obtained following a standardized protocol: peripheral venous blood was drawn from postoperative patients on the first daytime after surgery, while samples from healthy controls were collected uniformly during daytime hours.A volume of 2\u0026ndash;5 mL of blood was collected using additive-free specialized blood collection tubes. After ensuring complete evaporation of disinfectants, samples were gently inverted to mix and allowed to clot at room temperature for 1 hour. All samples were transported by dedicated personnel and labeled with patient names and hospital identification numbers to ensure traceability. Upon receipt, samples were immediately stored at \u0026minus;\u0026thinsp;80\u0026deg;C until further analysis.\u003c/p\u003e\u003cp\u003eThis standardized collection procedure effectively minimized anticoagulant interference and hemolysis risk, thereby ensuring high-quality serum samples for subsequent metabolomic analysis. The study protocol and sample collection procedures strictly adhered to the principles of the Declaration of Helsinki and were reviewed and approved by the Medical Ethics Committee of the First Affiliated Hospital of University of South China (Approval No: 2024LL1016001). Prior to participation, all enrolled patients with acute DeBakey type I aortic dissection or their legally authorized representatives provided written informed consent after full explanation of the study. The entire study was subject to ongoing supervision by the ethics committee, with no protocol deviations or ethical disputes occurring.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eEligibility Criteria\u003c/h3\u003e\n\u003cp\u003e Patients diagnosed with acute Stanford type A aortic dissection based on imaging and clinical manifestations were included, provided they met the surgical indication criteria as per the 2022 ESC Guidelines for the Diagnosis and Treatment of Aortic Diseases. Exclusion criteria comprised preoperative impaired consciousness or coma, defined as a Glasgow Coma Scale score\u0026thinsp;\u0026le;\u0026thinsp;8; the presence of multiple organ dysfunction syndrome meeting at least two organ failure criteria; or the requirement for sustained high-dose vasoactive drug support\u0026mdash;such as norepinephrine exceeding 0.5 \u0026micro;g/kg/min for a duration of 24 hours or longer\u0026mdash;to maintain circulatory stability.\u003c/p\u003e\n\u003ch3\u003eExperimental Procedures\u003c/h3\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eMetabolite Extraction\u003c/h2\u003e\u003cp\u003eMetabolites were extracted using a Starlid\u0026trade; workstation. A volume of 50 \u0026micro;L of each sample was mixed with 200 \u0026micro;L of extraction solution (methanol:acetonitrile\u0026thinsp;=\u0026thinsp;1:1, v/v, containing internal standards) and oscillated at 750 rpm for 5 minutes. After standing for another 5 minutes, the mixture was filtered through a protein precipitation plate, and the filtrate was collected. Quality control (QC) samples were prepared by pooling equal volumes of all sample filtrates.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eLC-MS/MS Analysis\u003c/h3\u003e\n\u003cp\u003eFor polar metabolites, LC-MS/MS analysis was performed using a Vanquish UHPLC system (Thermo Fisher Scientific) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] equipped with a Waters ACQUITY UPLC BEH Amide column (2.1 mm \u0026times; 50 mm, 1.7 \u0026micro;m) and coupled to an Orbitrap Exploris 120 mass spectrometer (Thermo Fisher). The mobile phase consisted of 25 mmol/L ammonium acetate and 25 mmol/L ammonia aqueous solution (pH\u0026thinsp;=\u0026thinsp;9.75) (phase A) and acetonitrile (phase B). The autosampler temperature was maintained at 4\u0026deg;C, and the injection volume was 2 \u0026micro;L. The Orbitrap Exploris 120 mass spectrometer was operated in information-dependent acquisition (IDA) mode, controlled by the acquisition software (Xcalibur, Thermo Fisher), which continuously evaluated full-scan MS spectra to trigger MS/MS acquisition. The electrospray ionization (ESI) source conditions were set as follows: sheath gas flow rate, 50 Arb; auxiliary gas flow rate, 15 Arb; capillary temperature, 320\u0026deg;C; full MS resolution, 60,000; MS/MS resolution, 15,000; collision energy using stepped normalized collision energy (SNCE) at 20, 30, and 40 eV; and spray voltages of 3.8 kV (positive ion mode) and 3.4 kV (negative ion mode).\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eData Preprocessing and Annotation\u003c/h2\u003e\u003cp\u003eRaw data were converted to mzXML format using ProteoWizard and processed with an in-house R-based pipeline built upon the XCMS package for feature detection, extraction, alignment, and integration. Metabolite identification was performed using R packages and AigenXDB (version 3.0). Reference: Zhou, Z., Luo, M., Zhang, H., Yin, Y., Cai, Y., \u0026amp; Zhu, Z. J. (2022).Metabolite annotation from knowns to unknowns through knowledgeguided multi-layer metabolic networking. Nature communications, 13(1),6656.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eQuality Control\u003c/h3\u003e\n\u003cp\u003eQC samples were employed to systematically monitor the reliability and reproducibility of the analytical process. The QC samples were prepared by pooling equal volumes of all experimental samples and were injected at intervals of every 10 experimental samples to assess instrumental drift and systematic error. The stability of the LC-MS system was evaluated by examining the extracted ion chromatograms (EICs) of isotopic internal standards in the QC samples, which allowed for assessment of retention time consistency and response stability. Potential system contamination was evaluated by comparing the EICs of internal standards in blank samples with those in QC samples. Additionally, the tightness of clustering of QC samples was assessed using principal component analysis, while data reproducibility was evaluated by calculating Pearson correlation coefficients between QC samples. The response stability of multiple isotopic internal standards throughout the analytical sequence was monitored, and the relative standard deviation (RSD) of their peak areas was calculated to evaluate overall data quality.\u003c/p\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003eData Analysis\u003c/h2\u003e\u003cp\u003e The feature peaks detected in this study were initially processed using relative standard deviation-based denoising. Missing values were imputed with half of the minimum value, and data were normalized using an internal standard-based method. The resulting data matrix, comprising feature peak numbers, sample names, and normalized peak areas, was imported into SIMCA version 18.0.1 (Sartorius Stedim Data Analytics AB, Umea, Sweden) for multivariate statistical analysis. The data were scaled and logarithmically transformed to reduce noise and mitigate the influence of high variance among variables. Unsupervised principal component analysis (PCA) was subsequently performed to visualize sample distribution and grouping patterns. Outliers were identified and excluded based on the 95% confidence interval in the PCA score plot.\u003c/p\u003e\u003cp\u003eTo investigate intergroup differences and identify significantly altered metabolites, supervised orthogonal partial least squares-discriminant analysis (OPLS-DA) was employed. The model's explanatory power (R\u0026sup2;) and predictive ability (Q\u0026sup2;) were evaluated using 7-fold cross-validation. A permutation test with 200 iterations was further conducted to assess model robustness and to obtain intercept values for R\u0026sup2; and Q\u0026sup2;. The Q\u0026sup2; intercept value reflects the model's resistance to overfitting and its overall reliability, with lower values indicating better performance. Variables were ranked based on the variable importance in projection (VIP) score from the first predictive component of the OPLS-DA model. Metabolites with VIP\u0026thinsp;\u0026gt;\u0026thinsp;1 and a p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 from Student\u0026rsquo;s t-test were considered statistically significant. Pathway enrichment analysis was subsequently performed using the KEGG and MetaboAnalyst databases.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eMetabolite Identification, Data Processing, and Intergroup Profiling\u003c/h2\u003e\n \u003cp\u003eUntargeted metabolomic analysis initially detected 43,513 feature peaks, as illustrated in Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ea. Following data preprocessing, 28,369 feature peaks were retained, among which 1,744 metabolites were confirmed with MS/MS secondary identification. The classification of these identified metabolites is presented in Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eb. After normalization, all samples were subjected to hierarchical clustering analysis, and a heatmap was generated (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ec). Clear separation between the AT (aortic dissection postoperative) and HC (healthy control) groups was observed, indicating systematic differences in their metabolic profiles.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003eEvaluation of Data Quality and Stability\u003c/h2\u003e\n \u003cp\u003eTo ensure the reliability of the metabolomic data, systematic quality control was implemented. First, examination of the extracted ion chromatograms (EICs) of isotopic internal standards in the QC samples revealed highly consistent retention times, sharp and symmetric peak shapes, and minimal fluctuations in response intensity (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ea, \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eb), indicating that the liquid chromatography-mass spectrometry (LC-MS) system remained stable throughout the entire sample analysis sequence. Meanwhile, comparison of the EICs of internal standards between blank samples and QC samples showed no detectable internal standard signals in the blanks, effectively ruling out potential system contamination (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ec, \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ed).\u003c/p\u003e\n \u003cp\u003eTo further evaluate the overall quality of the metabolomics data, we systematically investigated the stability of the metabolic profiles across all samples using principal component analysis (PCA). The results demonstrated that all quality control (QC) samples exhibited highly clustered distribution in the PCA score plot (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ea), indicating excellent stability of the LC-MS/MS analytical process and effective control of instrumental fluctuations and systematic errors. In striking contrast, the actual biological samples showed distinctly dispersed distribution, reflecting genuine intergroup biological differences. Further one-dimensional PCA-X distribution analysis of QC samples revealed that all quality control samples were distributed within \u0026plusmn;\u0026thinsp;2 standard deviations along the first principal component, with no significant trend observed according to the injection order, further confirming the high stability of the analytical system (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eb). Additionally, correlation analysis among QC samples showed Pearson correlation coefficients all greater than 0.93, demonstrating high reproducibility of metabolite quantification results (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ec). Finally, we validated quantitative accuracy by examining the response stability of isotopic internal standards: all six internal standards exhibited excellent response stability throughout the analytical sequence, with relative standard deviations (RSD) of peak areas ranging from 1.35% to 16.75%. Notably, five of these internal standards showed RSD values below 5.4% (Table\u0026nbsp;1). These results collectively demonstrate the reliability and accuracy of our data from multiple perspectives, providing a solid foundation for subsequent analyses.\u003c/p\u003e\n \u003cp\u003eTable\u0026nbsp;1. Response stability data of isotopic internal standards\u003c/p\u003e\n \u003cp\u003e\u003cimg 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\"\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003eAnalysis of Overall Metabolic Profile Characteristics\u003c/h2\u003e\n \u003cp\u003ePrincipal component analysis (PCA) revealed significant separation between the serum metabolic profiles of the aortic dissection postoperative (AT) group and the healthy control (HC) group (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003ea). The cumulative contribution rate of the first (PC1) and second (PC2) principal components was 64.1%, with PC1 accounting for 49.4% and PC2 for 14.7%. Samples from the AT group were predominantly distributed in the left side of the negative PC1 axis and the upper side of the positive PC2 axis, while HC group samples clustered in the right side of the positive PC1 axis and the lower side of the negative PC2 axis. The non-overlapping 95% confidence intervals between the two groups indicated significant alterations in metabolic profiles following surgery. To more reliably assess intergroup metabolite differences and classification correlations, orthogonal partial least squares-discriminant analysis (OPLS-DA) was employed. The results demonstrated clear separation between the AT and HC groups\u0026apos; metabolic profiles (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003eb). The first predictive component (t [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e] P) of the model explained 35.5% of the variation, while the first orthogonal component (t [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e] O) accounted for 15.4% of the variation, indicating the effectiveness of the OPLS-DA model in distinguishing the metabolic characteristics between the two groups. In the score plot, samples from the AT and HC groups showed distinct separation along the first predictive component axis with no overlapping distribution areas, further confirming significant postoperative changes in metabolic profiles. The reliability of the OPLS-DA model was confirmed through 200 permutation tests (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003ec\u0026ndash;d). The model\u0026apos;s explanatory power (R\u0026sup2;Y) and predictive ability (Q\u0026sup2;) reached 0.968 and 0.96, respectively. All permuted models exhibited significantly lower R\u0026sup2;Y and Q\u0026sup2;values compared to the original model, with the original parameters located at the extreme right of the random distribution (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). None of the 200 permuted models outperformed the original model. Furthermore, the Q\u0026sup2; intercept was \u0026minus;\u0026thinsp;1.45, substantially below the threshold of 0.05, indicating no overfitting in the model. These results collectively demonstrate that the OPLS-DA model robustly and significantly distinguishes the metabolic characteristics between postoperative aortic dissection patients and healthy individuals.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003eScreening and Identification of Key Differential Metabolites\u003c/h2\u003e\n \u003cp\u003eBased on combined univariate (t-test, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and multivariate (OPLS-DA, VIP\u0026thinsp;\u0026gt;\u0026thinsp;1) screening criteria, a total of 791 significantly differential metabolites were identified, including 416 upregulated and 375 downregulated metabolites in the postoperative (AT) group. As shown in the volcano plot (Fig. \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003ea), the top 10 most significantly upregulated and downregulated metabolites (20 in total) were selected for annotation (Additional Table 2).The Z-score distribution plot of differential metabolites (Fig. \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003eb) clearly displays the standardized abundance distribution of these 20 selected significant metabolites in the healthy control (HC) group and the aortic dissection postoperative (AT) group. As illustrated, the vast majority of metabolites exhibited distinctly opposite distribution patterns between the two groups. In the HC group, metabolites such as uridine, N-methylpropionamide, and phospholipid PC(18:4/20:3) showed Z-score values predominantly concentrated above the zero axis, indicating their abundances were higher than the average level across all samples. Conversely, in the AT group, these metabolites demonstrated significant shifts toward the negative side of the zero axis, suggesting substantially reduced abundances after surgery.In contrast, certain metabolites including 2-acetylthiazole and 2-methylbutyrylglycine, which already showed relatively low levels in the HC group (mean Z-score close to or less than zero), exhibited further distribution shifts toward the negative region in the AT group, indicating more pronounced downregulation trends. These visualization results were highly consistent with statistical analyses (VIP\u0026thinsp;\u0026gt;\u0026thinsp;1, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, and large absolute values of Log₂(Fold Change)), collectively confirming the extensive metabolic disturbances in patients following aortic dissection surgery. Hierarchical clustering analysis (using Euclidean distance matrix and complete linkage method) of the top 10 significantly upregulated and downregulated metabolites (20 in total) revealed distinct clustering patterns (Fig. \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003ec). The metabolites were divided into two main clusters: Cluster A contained 10 metabolites including N-Methylpropionamide and 2-Acetylthiazole, while Cluster B comprised 10 metabolites including Uridine and PC(22:6(4Z,7Z,10Z,13Z,16Z,19Z)/22:6(4Z,7Z,10Z,13Z,16Z,19Z)). Sample grouping analysis demonstrated that healthy control (HC) samples predominantly distributed along the left branch of the heatmap, whereas postoperative (AT) samples clustered on the right branch. Regarding expression patterns, Cluster A metabolites exhibited consistently low expression intensity in the AT group, while Cluster B metabolites showed consistently high expression intensity in the AT group.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n \u003ch2\u003eDistribution Characteristics of Key Differential Metabolites\u003c/h2\u003e\n \u003cp\u003eBoxplot analysis (integrated and presented in Fig. \u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003e) clearly revealed extremely significant intergroup differences in the concentrations of four key metabolites between the postoperative (AT) and healthy control (HC) groups (all p-values\u0026thinsp;\u0026lt;\u0026thinsp;1\u0026times;10⁻\u0026sup2;⁰). Specifically, the median concentrations of all four metabolites (uridine, phospholipid PC(18:4/20:3), N-methylpropionamide, and 2-acetylthiazole) were significantly lower in the AT group compared to the HC group. Beyond the overall concentration reduction, each metabolite exhibited unique distribution characteristics: uridine showed a narrower distribution range (IQR) in the AT group; phospholipid PC(18:4/20:3) displayed more high-value outliers in the HC group; N-methylpropionamide exhibited right-skewed distribution (longer upper whisker) in the AT group; while 2-acetylthiazole showed similar IQR widths between groups but completely non-overlapping distribution areas (see Supplementary Materials for boxplots of remaining metabolites).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n \u003ch2\u003eVisualization of the Magnitude of Changes in Differential Metabolites\u003c/h2\u003e\n \u003cp\u003eThe magnitude of changes in the top 10 significantly upregulated and downregulated metabolites (20 in total) was jointly analyzed using a needle plot (Fig. \u003cspan class=\"InternalRef\"\u003e8\u003c/span\u003ea) and a radar chart (Fig. \u003cspan class=\"InternalRef\"\u003e8\u003c/span\u003eb). The needle plot, with log₂ Fold Change as the x-axis and VIP value gradient as color depth, identified N-methylpropionamide (log₂FC = -3.66, VIP\u0026thinsp;=\u0026thinsp;1.63) as the most downregulated metabolite, while the glutamine-threonine dipeptide (Gln-Thr, log₂FC\u0026thinsp;=\u0026thinsp;4.59, VIP\u0026thinsp;=\u0026thinsp;1.85) was the most upregulated metabolite. All metabolites exhibited *** level significance (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The downregulated group was predominantly distributed in the negative range (log₂FC: -1.72 to -3.66), while the upregulated group was concentrated in the positive range (log₂FC: 1.30 to 4.59). Further visualization via radar chart intuitively displayed the expression change patterns of the top 10 significantly upregulated and downregulated metabolites, represented by log₂(Fold Change). As shown in Fig. \u003cspan class=\"InternalRef\"\u003e8\u003c/span\u003eb, all 20 metabolites reached extremely significant levels (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The trajectory of upregulated metabolites was largely located outside the peripheral grid line (log₂FC\u0026thinsp;=\u0026thinsp;1), with the dipeptide Gln-Thr showing the most pronounced change (log₂FC\u0026thinsp;=\u0026thinsp;4.59). In contrast, the trajectory of downregulated metabolites was concentrated in the central and inner regions, with N-methylpropionamide exhibiting the greatest degree of downregulation (log₂FC = -3.66). The needle and radar charts clearly reveal bidirectional and substantial concentration changes in serum metabolites following aortic dissection surgery, demonstrating distinct spatial distribution patterns between upregulated and downregulated metabolites in terms of the magnitude of change.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\n \u003ch2\u003eMetabolite Correlation Interaction Network\u003c/h2\u003e\n \u003cp\u003eIntegrated analysis based on Pearson correlation network (Fig. \u003cspan class=\"InternalRef\"\u003e9\u003c/span\u003ea) and chord diagram (Fig. \u003cspan class=\"InternalRef\"\u003e9\u003c/span\u003eb) revealed core features of the postoperative serum metabolite interaction network. The study found that the downregulated metabolite cluster (e.g., 2-ketobutyric acid, 6-hydroxynorleucine) exhibited significant intra-cluster synergistic effects, characterized by strong positive correlations (r\u0026thinsp;\u0026gt;\u0026thinsp;0.8). Correspondingly, the upregulated metabolite cluster (e.g., uridine, LPA(20:4)) also showed significant positive correlations (e.g., r\u0026thinsp;=\u0026thinsp;0.848 between uridine and LPA(20:4)). More importantly, strong negative correlations (r \u0026lt; -0.7) were widely observed between the two metabolite clusters. Among them, the most representative were the strong negative correlation between the most downregulated metabolite, N-methylpropionamide, and the most upregulated metabolite, glutamine-threonine dipeptide (r = -0.804), as well as the significant negative correlation between uridine and 2-acetylthiazole (r = -0.886). These relationships were further validated by chord diagram visualization. The results indicated significant intra-cluster synergy and inter-cluster antagonism among metabolites. Downregulated metabolites (e.g., uridine, N-methylpropionamide) formed tightly connected positive correlation clusters (mostly thick red chords), indicating their coordinated downregulation after surgery. In contrast, upregulated and downregulated metabolite clusters were generally connected by blue negative correlation chords, demonstrating systematic antagonistic relationships. For example, strong negative correlations were observed between the most downregulated metabolite, N-methylpropionamide, and certain upregulated metabolites. Furthermore, the diagram clearly illustrated the participation of different superclasses of metabolites in postoperative metabolic perturbations, with lipids and organic acids constituting the major nodes in the network.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\n \u003ch2\u003eAnalysis of Metabolic Pathway Perturbations: KEGG Pathway Enrichment Analysis\u003c/h2\u003e\n \u003cp\u003eTo gain deeper insights into the functional characteristics and potential biological significance of the differential metabolites identified in the serum metabolomics data of postoperative aortic dissection patients, we performed a comprehensive bioinformatics analysis.. The KEGG classification analysis (Fig. \u003cspan class=\"InternalRef\"\u003e10\u003c/span\u003ea) revealed that these metabolites were primarily enriched in pathways related to amino acid metabolism, carbohydrate metabolism, and membrane transport. The perturbation of these pathways was further quantified using Differential Abundance (DA) Score analysis (Fig. \u003cspan class=\"InternalRef\"\u003e10\u003c/span\u003eb). This analysis delineated the direction and magnitude of changes within the enriched pathways. In amino acid metabolism, we observed a marked reduction in the abundance of D-amino acid metabolism (DA Score = -0.8) and glycine, serine, and threonine metabolism (DA Score = -0.4). Concurrently, energy metabolism pathways were significantly suppressed, as evidenced by the downregulation of 2-oxocarboxylic acid metabolism (DA Score = -0.43) and central carbon metabolism in cancer (DA Score = -0.86). Furthermore, pathways associated with membrane transport, such as ABC transporters (DA Score = -0.30), also showed decreased abundance. The enrichment bubble plot (Fig. \u003cspan class=\"InternalRef\"\u003e10\u003c/span\u003ec) provided a consolidated view of both the statistical significance and the magnitude of these pathway alterations. This analysis validated the above findings, confirming that ABC transporters (enrichment factor\u0026thinsp;=\u0026thinsp;0.167, p\u0026thinsp;=\u0026thinsp;1.13\u0026times;10⁻\u0026sup1;\u0026sup3;) and aminoacyl-tRNA biosynthesis (enrichment factor\u0026thinsp;=\u0026thinsp;0.269, p\u0026thinsp;=\u0026thinsp;1.22\u0026times;10⁻\u0026sup1;\u0026sup1;) were among the most significantly perturbed pathways. Key amino acid metabolism pathways, including D-amino acid metabolism (p\u0026thinsp;=\u0026thinsp;5.99\u0026times;10⁻⁶) and glycine, serine, and threonine metabolism (p\u0026thinsp;=\u0026thinsp;1.79\u0026times;10⁻⁷), as well as energy-related pathways like 2-oxocarboxylic acid metabolism (p\u0026thinsp;=\u0026thinsp;1.00\u0026times;10⁻⁵), were all robustly confirmed. Collectively, the results from these complementary analyses demonstrate that aortic dissection surgery induces extensive reprogramming of amino acid metabolism, energy homeostasis, and membrane transport processes.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\n \u003ch2\u003eIdentification of Key Perturbed Pathways through Enrichment and Topological Analysis\u003c/h2\u003e\n \u003cp\u003eTo further identify core pathways with both statistical significance and biological impact from these enriched pathways, topological analysis based on p-value and impact value was subsequently performed. This analysis helps identify pathways that occupy key positions within the overall metabolic network. First, the differential metabolites were matched against the KEGG and PubChem databases (Supplementary Table 2), followed by metabolic pathway analysis based on the human pathway database. Pathways with the greatest statistical significance and biological impact were screened by calculating the enrichment degree (p-value) and topological impact value (Impact) (Supplementary Table 3). Significance analysis revealed that the differential metabolites were significantly enriched in multiple core metabolic pathways (Fig. \u003cspan class=\"InternalRef\"\u003e11\u003c/span\u003ea). Among them, the aminoacyl-tRNA biosynthesis pathway (p\u0026thinsp;=\u0026thinsp;1.02\u0026times;10⁻⁴, Impact\u0026thinsp;=\u0026thinsp;0.225) contained 13 differential metabolites, including glycine (C00037) and L-glutamine (C00064). The glycine, serine, and threonine metabolism pathway (p\u0026thinsp;=\u0026thinsp;6.93\u0026times;10⁻⁴, Impact\u0026thinsp;=\u0026thinsp;0.380) involved 9 metabolites; the nitrogen metabolism pathway (p\u0026thinsp;=\u0026thinsp;7.42\u0026times;10⁻⁴, Impact\u0026thinsp;=\u0026thinsp;0.001) contained 8 metabolites; and the arginine and proline metabolism pathway (p\u0026thinsp;=\u0026thinsp;1.93\u0026times;10⁻\u0026sup3;, Impact\u0026thinsp;=\u0026thinsp;0.203) involved 11 metabolites. Topological analysis (Fig. \u003cspan class=\"InternalRef\"\u003e11\u003c/span\u003eb) further revealed high-impact metabolic pathways: the alanine, aspartate, and glutamate metabolism pathway (Impact\u0026thinsp;=\u0026thinsp;0.649) and the taurine and hypotaurine metabolism pathway (Impact\u0026thinsp;=\u0026thinsp;0.433). Additionally, the pantothenate and CoA biosynthesis pathway (p\u0026thinsp;=\u0026thinsp;0.012, Impact\u0026thinsp;=\u0026thinsp;0.038) and the pyruvate metabolism pathway (p\u0026thinsp;=\u0026thinsp;0.017, Impact\u0026thinsp;=\u0026thinsp;0.240) also showed significant alterations. Notably, sphingosine (C00319) in sphingolipid and fatty acid metabolism pathways, palmitoylcarnitine (C02990), and indolelactic acid (C02043) in the tryptophan metabolism pathway were significantly altered.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\n \u003ch2\u003eIntegrated Network Enrichment Analysis Reveals Global Characteristics of the Postoperative Metabolic Regulatory Network\u003c/h2\u003e\n \u003cp\u003eNetwork Enrichment Analysis Based on KEGG Database Reveals Global Characteristics of the Metabolic Regulatory Network Following Aortic Dissection Surgery (Fig. \u003cspan class=\"InternalRef\"\u003e12\u003c/span\u003e). This analysis integrated multi-level information including metabolic pathways, modules, enzymes, reactions, and metabolites to construct a comprehensive metabolic interaction network. The results demonstrated significant enrichment features (p\u0026thinsp;\u0026lt;\u0026thinsp;1\u0026times;10⁻⁵) in multiple key metabolic pathways, including taurine and hypotaurine metabolism (hsa00430, p\u0026thinsp;=\u0026thinsp;1.54\u0026times;10⁻⁵), ABC transporters (hsa02010, p\u0026thinsp;=\u0026thinsp;8.60\u0026times;10⁻⁶), sphingolipid signaling pathway (hsa04071, p\u0026thinsp;=\u0026thinsp;4.99\u0026times;10⁻⁵), mTOR signaling pathway (hsa04150, p\u0026thinsp;=\u0026thinsp;1\u0026times;10⁻⁶), and apoptosis (hsa04210, p\u0026thinsp;=\u0026thinsp;1\u0026times;10⁻⁶). Core metabolic nodes in the network involved amino acid metabolism-related compounds (e.g., glycine C00037, L-alanine C00041, and L-aspartate C00049), lipid metabolism-related molecules (e.g., sphingosine C00319, sphingomyelin C00550, and 1-acyl-sn-glycero-3-phosphocholine C04230), as well as energy metabolism intermediates (e.g., taurine C00245 and hypotaurine C00519). Key enzyme nodes primarily included sphingolipid metabolism-related enzymes (e.g., sphingosine kinase EC 2.7.1.91 and sphingomyelin synthase EC 2.7.8.27), amino acid metabolism enzymes (e.g., glycine amidinotransferase EC 2.1.4.1 and L-lactate dehydrogenase EC 1.1.1.27), and energy metabolism enzymes (e.g., xanthine dehydrogenase EC 1.17.1.4 and Na⁺/K⁺-ATPase EC 7.2.2.13). This network analysis clearly illustrates the distribution characteristics and interrelationships of differential metabolites within metabolic pathways, providing a systems-level perspective for understanding postoperative metabolic disturbances.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\n \u003ch2\u003eDifferential Metabolites Demonstrate Excellent Diagnostic Value Based on ROC Curve Analysis\u003c/h2\u003e\n \u003cp\u003eEvaluation of the diagnostic efficacy of differential metabolites through ROC curve analysis revealed that multiple metabolites exhibited outstanding classification performance in distinguishing postoperative aortic dissection patients (AT group) from healthy controls (HC group) (Supplementary materials). Among them, uridine, phosphatidylcholine PC(18:4/20:3), N-methylpropionamide, and 2-acetylthiazole all achieved AUC values of 1.0 (95% CI: 1.0\u0026ndash;1.0), indicating perfect discriminatory ability in the training set. Additionally, metabolites such as oxamate (AUC\u0026thinsp;=\u0026thinsp;1.0) and 3-amino-4-hydroxyphenyl sulfone (AUC\u0026thinsp;=\u0026thinsp;1.0) also demonstrated exceptionally high diagnostic potential. Further analysis showed that these metabolites exhibited excellent specificity and sensitivity. For example, uridine at a threshold of 0.18 achieved a specificity of 96.7% and a sensitivity of 100%, while PC(18:4/20:3) at a threshold of 0.13 showed a specificity of 100% and a sensitivity of 86.7%. These results suggest that these metabolites may serve as potential biomarkers for diagnosis or monitoring following aortic dissection surgery.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eMetabolomics, as a major branch of systems biology, provides a powerful tool for elucidating the metabolic basis of disease occurrence and progression by systematically analyzing the global changes of small-molecule metabolites within organisms. In recent years, with the rapid advancement of metabolomic technologies, its application in cardiovascular disease research has become increasingly widespread. This technology not only aids in identifying metabolic biomarkers associated with diseases but also reveals potential metabolic pathway abnormalities, thereby offering new perspectives and methods for the diagnosis, prognostic assessment, and treatment strategies of cardiovascular diseases [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThis study employed untargeted metabolomics technology to conduct, for the first time, a comprehensive and systematic comparison of serum metabolic profiles between postoperative patients with acute DeBakey type I aortic dissection and a healthy population, revealing characteristic postoperative metabolic reprogramming patterns. The results showed significant differences in serum metabolic profiles between postoperative patients and the healthy control group. Through multivariate statistical analysis, a total of 791 significantly differential metabolites were identified, with 416 upregulated and 375 downregulated, indicating that patients undergo substantial metabolic remodeling after aortic dissection surgery. This finding is consistent with multiple studies. Macrophage metabolic reprogramming plays a key role in the progression of aortic dissection, particularly by promoting vascular inflammation, extracellular matrix degradation, and elastic lamina fragmentation through the HIF-1α-ADAM17 pathway, thereby exacerbating the condition [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Furthermore, multi-omics studies have shown that FABP5\u0026thinsp;+\u0026thinsp;macrophages differentiate into a pro-inflammatory phenotype upon stimulation by metabolic substrates, releasing large quantities of cytokines that further drive the pathological process of aortic dissection [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. These mechanisms collectively support the notion of intense metabolic alterations following surgery.\u003c/p\u003e\u003cp\u003ePathway analysis further highlighted the central role of the aminoacyl-tRNA biosynthesis pathway. As a critical hub connecting metabolism and protein translation, this pathway is not only responsible for the correct coupling of amino acids to their cognate tRNAs, ensuring translational fidelity, but is also extensively involved in processes linking cellular metabolism and translational control [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Dysregulation of aminoacyl-tRNA synthetase function may impact the rate and accuracy of protein synthesis, thereby interfering with physiological processes such as postoperative tissue repair and immune responses [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Concurrently, the significant enrichment of amino acid metabolic pathways\u0026mdash;including glycine, serine, and threonine metabolism; arginine and proline metabolism; and D-amino acid metabolism\u0026mdash;suggests that these pathways play important roles in disease progression. Studies have shown that the plasma amino acid profiles of aortic dissection (AD) patients differ significantly from those with coronary heart disease (CHD), with notable changes in levels of amino acids such as glycine, serine, and proline, particularly in acute AD [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. This indicates that the body is in a state of hypercatabolism post-surgery, mobilizing amino acids in large quantities for energy production, acute-phase protein synthesis, and tissue repair. Following cardiac surgery, especially with cardiopulmonary bypass, protein catabolism is enhanced, and the degradation of amino acids such as valine, leucine, and isoleucine is exacerbated, which may be associated with postoperative complications like acute kidney injury [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTopological analysis further identified several high-impact core pathways, among which the alterations in taurine and hypotaurine metabolism are particularly noteworthy. These amino acid derivatives possess antioxidant and membrane-stabilizing functions, and their metabolic disturbances are likely closely related to intraoperative ischemia-reperfusion injury. Research indicates that taurine can mitigate ischemia-reperfusion injury by stabilizing cell membranes and scavenging free radicals [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The postoperative changes in taurine and hypotaurine levels may reflect the body's adaptive response to oxidative stress. Taurine levels are significantly elevated in models of hepatic ischemia-reperfusion [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], and hypotaurine, as its precursor, may exert protective effects through similar mechanisms. Metabolomic studies have already identified taurine as a differential metabolite in the serum of aortic dissection patients [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], further supporting its potential value in postoperative metabolic regulation.\u003c/p\u003e\u003cp\u003eThese pathway perturbations reflect specific pathophysiological alterations: The significant downregulation of energy metabolism-related metabolites such as uridine, along with changes in multiple key intermediates of the tricarboxylic acid (TCA) cycle and 2-oxocarboxylic acid metabolism, suggests impaired mitochondrial energy production and severe dysregulation of the body's energy metabolism. Uridine, as a nucleotide precursor, participates in UTP/ATP synthesis and glycogen metabolism [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]; its downregulation may lead to insufficient energy supply, adversely affecting postoperative recovery [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Similar phenomena have been reported in other cardiovascular diseases. For instance, maladaptive right ventricular remodeling in pulmonary hypertension is associated with disturbances in TCA cycle intermediates [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. The current results provide further evidence that postoperative energy reprogramming in aortic dissection is linked to antioxidant pathways, as suggested in our earlier work [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. abnormal TCA cycle and amino acid metabolism are also observed in abdominal aortic aneurysms [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. These consistent findings suggest that mitochondrial dysfunction may be a common pathological basis for cardiovascular diseases.Secondly, the significant enrichment of various amino acid metabolic pathways (such as glycine, serine, and threonine metabolism, and branched-chain amino acid metabolism) collectively confirms that the body is in a state of hypercatabolism post-surgery. In this state, amino acids are extensively mobilized, being consumed as an energy source on one hand, and utilized for the synthesis of acute-phase proteins and tissue repair processes on the other. This finding is highly consistent with the altered protein metabolism observed in patients following cardiac surgery, particularly those who have undergone cardiopulmonary bypass [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Furthermore, the significant alterations in phosphatidylcholine and sphingolipid metabolism may reflect surgery-induced erythrocyte destruction, vascular endothelial injury, or compromised mitochondrial membrane integrity. The observed downregulation of phosphatidylcholines (e.g., PC(18:4/20:3)) and various sphingolipids in this study aligns with previous research: these membrane lipid components are often significantly reduced in the serum of patients with acute aortic dissection [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Sphingolipid metabolism not only plays a crucial role in the post-myocardial infarction repair phase [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] but is also persistently dysregulated in the progression of cardiovascular diseases like atherosclerosis [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], underscoring the core importance of these metabolites in cardiovascular pathophysiology. Particularly noteworthy is that the downregulation of the ABC transporter pathway may have multifaceted and profound impacts on postoperative metabolic homeostasis. This pathway acts as a \"gatekeeper\" in the transmembrane transport of lipids, drugs, toxins, and various metabolites [\u003cspan additionalcitationids=\"CR31 CR32 CR33\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Its functional inhibition could lead to multiple consequences: firstly, it may affect lipid metabolism (e.g., reverse cholesterol transport), exacerbating dyslipidemia [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]; secondly, it could impede the timely efflux of intracellular metabolic waste products, leading to their accumulation and potentially inducing damage such as oxidative stress; thirdly, it may alter drug distribution and metabolism, affecting drug efficacy and increasing the risk of adverse reactions [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Therefore, the downregulation of ABC transporters may represent a potential key link connecting postoperative metabolic disturbances to clinical complications (e.g., altered drug sensitivity, toxin accumulation).\u003c/p\u003e\u003cp\u003eFurther correlation network analysis revealed intricate regulatory relationships among the metabolites. The differential metabolites displayed distinct co-expression patterns: strong positive correlations (r\u0026thinsp;\u0026gt;\u0026thinsp;0.8) were observed within the downregulated metabolite cluster (e.g., between 2-ketobutyric acid and 6-hydroxynorleucine), while the upregulated metabolites (e.g., uridine and LPA(20:4)) also exhibited high internal synergy (r\u0026thinsp;=\u0026thinsp;0.848). More importantly, strong antagonistic interactions (r \u0026lt; -0.7) were prevalent between the upregulated and downregulated metabolite clusters. Significant negative correlations were identified, for instance, between N-methylpropionamide and the glutamine-threonine dipeptide (r = -0.804), and between uridine and 2-acetylthiazole (r = -0.886). This highly organized metabolic network reprogramming indicates that the postoperative metabolic alterations constitute a systematic biological process. Metabolites interact and co-regulate each other through a sophisticated network, collectively defining the overall metabolic disturbance profile following surgery.\u003c/p\u003e\u003cp\u003eThis study also identified a panel of metabolites with potential clinical value as biomarkers. Metabolites such as uridine, phosphatidylcholine PC(18:4/20:3), N-methylpropionamide, and 2-acetylthiazole demonstrated exceptional discriminatory power (AUC\u0026thinsp;=\u0026thinsp;1.0), enabling accurate differentiation between postoperative patients and healthy individuals. These findings offer novel molecular targets for postoperative metabolic monitoring.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, this metabolomic investigation delineates a profound metabolic upheaval in patients following surgical repair of acute aortic dissection. The identified reprogramming, characterized by coherent perturbations in pathways critical for protein synthesis, energy homeostasis, and membrane transport, underscores a systemic biological response to major cardiovascular surgery. The robust discriminatory capacity of the discovered metabolic signature not only offers promising biomarkers for postoperative assessment but, more importantly, provides a metabolic framework for understanding the pathophysiology of recovery. These insights pave the way for future research aimed at determining whether modulating these metabolic pathways can positively influence clinical outcomes.\u003c/p\u003e\u003cdiv id=\"Sec25\" class=\"Section2\"\u003e\u003ch2\u003eLimitations\u003c/h2\u003e\u003cp\u003eThis study has several limitations. First, as a single-center observational study with a limited sample size, the findings require further validation in larger-scale, multi-center prospective cohorts in the future. Second, while the study revealed associations between metabolites and pathways, the causal biological mechanisms have not been elucidated through functional experiments. Finally, the relationship between these metabolic markers and long-term clinical outcomes in patients warrants further exploration.\u003c/p\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe metabolomics dataset generated and analyzed during the current study is not publicly available due to patient privacy and ethical restrictions but is available from the corresponding author on reasonable request. The data supporting the findings of this study are included within the article and its supplementary materials. All materials and protocols used in this study are described in detail in the 'Materials and Methods' section. Clinical samples were used under the approval of the Medical Ethics Committee of the First Affiliated Hospital of University of South China.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYuji Xiao\u0026nbsp;designed the study, performed the LC-MS-based metabolomic experiments, conducted data analysis, and drafted the manuscript.\u0026nbsp;Jia Liu\u0026nbsp;and\u0026nbsp;Wanru Ma\u0026nbsp;contributed equally to clinical data collection and sample management from the First Affiliated Hospital cohort.\u0026nbsp;Haonan Zhang\u0026nbsp;and\u0026nbsp;Heng Yang\u0026nbsp;optimized metabolite extraction protocols and conducted multivariate statistical analyses.\u0026nbsp;Juan Wu\u0026nbsp;performed statistical validation.\u0026nbsp;Jun Tang\u0026nbsp;provided valuable clinical insights and contributed to the discussion of the results.\u0026nbsp;Yucai Huang\u0026nbsp;participated in data curation.\u0026nbsp;Yaoguang Feng\u0026nbsp;provided essential clinical resources and oversight. Corresponding author\u0026nbsp;Zhengwen Lei\u0026nbsp;conceived the project, secured funding, provided overall supervision, and revised the manuscript critically for important intellectual content. All authors reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics Approval and Consent to Participate: This study was approved by the Medical Ethics Committee of the First Affiliated Hospital of University of South China (Approval No: 2024LL1016001). Written informed consent was obtained from all participants or their legal guardians prior to enrollment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003cbr\u003e\u003c/strong\u003eThis study was supported by colleagues from the Department of Thoracic and Cardiovascular Surgery, Health Management Center, and Medical Records Room of the First Affiliated Hospital of University of South China. We sincerely appreciate \u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by grant from Hunan Provincial Natural Science Foundation (2023JJ50152) and Hengyang City Science and Technology Innovation Plan (Hengke Zi [2023] No. 14).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eChandiramani A, Al-Tawil M, Elleithy A, et al. Organ-specific malperfusion in acute type A aortic dissection: epidemiological meta-analysis of incidence rates[J]. BJS open, 2025, 9(1): zrae146.\u003c/li\u003e\n\u003cli\u003eYamashita Y, Joo K, Okamoto K, et al. Postoperative Maximal Aortic Diameter is a Significant Predictor of Dilation of the Residual Dissected Aorta after Aortic Replacement for Acute Debakey Type I Aortic Dissection[J]. 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Frontiers in Pharmacology, 2024, 15: 1423416.\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":"Aortic dissection surgery, Postoperative metabolism, Untargeted metabolomics, Metabolic reprogramming, KEGG pathway","lastPublishedDoi":"10.21203/rs.3.rs-7708816/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7708816/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eTo apply untargeted metabolomics technology to systematically analyze changes in the serum metabolic profiles of patients after surgery for acute DeBakey type I aortic dissection, aiming to explore postoperative metabolic characteristics and evaluate their potential application value.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis study enrolled 30 postoperative patients (AT) and 30 healthy controls (HC). Metabolite detection was performed using ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS). After strict quality control, multivariate statistical analysis was employed to screen for differential metabolites, followed by KEGG pathway enrichment and topological analysis. The discriminatory performance of key metabolites was assessed using receiver operating characteristic (ROC) curves.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eA total of 791 differential metabolites were identified. The metabolic profiles showed significant separation between the postoperative and healthy control groups. The differential metabolites were primarily enriched in pathways such as aminoacyl-tRNA biosynthesis, glycine/serine/threonine metabolism, and ABC transporters. Several metabolites exhibited promising discriminatory power.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThis study reveals extensive metabolic reprogramming following aortic dissection surgery, indicating synergistic perturbations in amino acid metabolism, energy metabolism, and membrane transport pathways. The identified metabolic features provide a potential molecular basis for postoperative metabolic monitoring.\u003c/p\u003e","manuscriptTitle":"Serum Metabolomics Reveals Metabolic Reprofiling and Perturbed Pathways after Aortic Dissection Surgery","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-17 09:53:54","doi":"10.21203/rs.3.rs-7708816/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":"58b84ac0-6d7f-4aaf-9358-91ff8b80c5a6","owner":[],"postedDate":"November 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-09T01:08:43+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-17 09:53:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7708816","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7708816","identity":"rs-7708816","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}