{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T05:35:44Z","timestamp":1792647344929,"version":"4.5.0"},"reference-count":47,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,2]],"date-time":"2025-01-02T00:00:00Z","timestamp":1735776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82070312"],"award-info":[{"award-number":["82070312"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82373868"],"award-info":[{"award-number":["82373868"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Septic cardiomyopathy (SCM) is a severe cardiac complication of sepsis, characterized by cardiac dysfunction with limited effective treatments. This study aimed to identify repurposable drugs for SCM by integrated multi-omics and network analyses. Methods: We generated a mouse model of SCM induced by lipopolysaccharide (LPS) and then obtained comprehensive metabolic and genetic data from SCM mouse hearts using ultra-performance liquid chromatography\u2013tandem mass spectrometry (UPLC\u2013MS\/MS) and RNA sequencing (RNA-seq). Using network proximity analysis, we screened for FDA-approved drugs that interact with SCM-associated pathways. Additionally, we tested the cardioprotective effects of two drug candidates in the SCM mouse model and explored their mechanism-of-action in H9c2 cells. Results: Network analysis identified 129 drugs associated with SCM, which were refined to 14 drug candidates based on strong network predictions, proven anti-infective effects, suitability for ICU use, and minimal side effects. Among them, acetaminophen and pyridoxal phosphate significantly improved cardiac function in SCM moues, as demonstrated by the increased ejection fraction (EF) and fractional shortening (FS), and the reduced levels of cardiac injury biomarkers: B-type natriuretic peptide (BNP) and cardiac troponin I (cTn-I). In vitro assays revealed that acetaminophen inhibited prostaglandin synthesis, reducing inflammation, while pyridoxal phosphate restored amino acid balance, supporting cellular function. These findings suggest that both drugs possess protective effects against SCM. Conclusions: This study provides a robust platform for drug repurposing in SCM, identifying acetaminophen and pyridoxal phosphate as promising candidates for clinical translation, with the potential to improve treatment outcomes in septic patients with cardiac complications.<\/jats:p>","DOI":"10.3390\/ph18010043","type":"journal-article","created":{"date-parts":[[2025,1,2]],"date-time":"2025-01-02T10:32:26Z","timestamp":1735813946000},"page":"43","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Multi-Omics and Network-Based Drug Repurposing for Septic Cardiomyopathy"],"prefix":"10.3390","volume":"18","author":[{"given":"Pei-Pei","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Yue","family":"Yu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing-Qing","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Jun","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Xuan","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Nanjing Drum Tower Hospital, Clinical College, Nanjing Medical University, Nanjing 210008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin","family":"Huang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China"},{"name":"Department of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Ban","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China"},{"name":"State Key Laboratory of Frigid Zone Cardiovascular Diseases, Ministry of Science and Technology, Harbin Medical University, Harbin 150081, China"},{"name":"Key Laboratory of Cardiovascular Research, Ministry of Education, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Carbone, F., Liberale, L., Preda, A., Schindler, T.H., and Montecucco, F. (2022). Septic Cardiomyopathy: From Pathophysiology to the Clinical Setting. Cells, 11.","DOI":"10.3390\/cells11182833"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1038\/s41569-020-00492-2","article-title":"Pathophysiology of Sepsis-Induced Cardiomyopathy","volume":"18","author":"Hollenberg","year":"2021","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, Regional, and National Sepsis Incidence and Mortality, 1990\u20132017: Analysis for the Global Burden of Disease Study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e009160","DOI":"10.1161\/JAHA.118.009160","article-title":"Tako-Tsubo Cardiomyopathy in Severe Sepsis: Nationwide Trends, Predictors, and Outcomes","volume":"7","author":"Vallabhajosyula","year":"2018","journal-title":"J. Am. Heart Assoc. Cardiovasc. Cerebrovasc. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s40560-021-00549-5","article-title":"Afterload-Related Cardiac Performance Identifies Cardiac Impairment and Associates with Outcome in Patients with Septic Shock: A Retrospective Cohort Study","volume":"9","author":"Chen","year":"2021","journal-title":"J. Intensiv. Care"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1161\/CIRCULATIONAHA.106.678359","article-title":"Sepsis and the Heart","volume":"116","author":"Merx","year":"2007","journal-title":"Circulation"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2254","DOI":"10.1016\/j.chest.2020.12.016","article-title":"Impact of Right Ventricular Dysfunction on Short-Term and Long-Term Mortality in Sepsis A Meta-Analysis of 1373 Patients","volume":"159","author":"Vallabhajosyula","year":"2021","journal-title":"Chest"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.chest.2018.08.1037","article-title":"The Septic Heart Current Understanding of Molecular Mechanisms and Clinical Implications","volume":"155","author":"Martin","year":"2019","journal-title":"Chest"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1089\/ars.2021.0027","article-title":"Oxidative Stress and Endothelial Dysfunction in Sepsis and Acute Inflammation","volume":"35","author":"Joffre","year":"2021","journal-title":"Antioxid. Redox Signal."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1007\/s11306-019-1615-1","article-title":"Metabolomics Facilitates the Discovery of Metabolic Biomarkers and Pathways for Ischemic Stroke: A Systematic Review","volume":"15","author":"Ke","year":"2019","journal-title":"Metabolomics"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1007\/s00134-018-5242-5","article-title":"A Global Perspective on Vasoactive Agents in Shock","volume":"44","author":"Annane","year":"2018","journal-title":"Intensiv. Care Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s11886-020-01277-2","article-title":"Sepsis-Induced Cardiomyopathy: A Comprehensive Review","volume":"22","author":"Sternberg","year":"2020","journal-title":"Curr. Cardiol. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1164\/rccm.201806-1034OC","article-title":"Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER). A Randomized Trial","volume":"199","author":"Permpikul","year":"2019","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"S72","DOI":"10.21037\/jtd.2019.12.50","article-title":"Early Norepinephrine Use in Septic Shock","volume":"12","author":"Hamzaoui","year":"2020","journal-title":"J. Thorac. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"107825","DOI":"10.1016\/j.isci.2023.107825","article-title":"Decoding Molecular Signature on Heart of Septic Mice with Distinct Left Ventricular Ejection Fraction","volume":"26","author":"Zhang","year":"2023","journal-title":"iScience"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"104599","DOI":"10.1016\/j.jprot.2022.104599","article-title":"Integrated Insights into the Mechanisms Underlying Sepsis-Induced Myocardial Depression Using a Quantitative Global Proteomic Analysis","volume":"262","author":"Yang","year":"2022","journal-title":"J. Proteom."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Yan, X., Zhang, Y.-L., Han, X., Li, P.-B., Guo, S.-B., and Li, H.-H. (2022). Time Series Transcriptomic Analysis by RNA Sequencing Reveals a Key Role of PI3K in Sepsis-Induced Myocardial Injury in Mice. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.903164"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"477","DOI":"10.2147\/JIR.S266012","article-title":"Comprehensive Evaluation of Lipopolysaccharide-Induced Changes in Rats Based on Metabolomics","volume":"13","author":"Geng","year":"2020","journal-title":"J. Inflamm. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e025310","DOI":"10.1161\/JAHA.122.025310","article-title":"Age-Independent Cardiac Protection by Pharmacological Activation of Beclin-1 During Endotoxemia and Its Association With Energy Metabolic Reprograming in Myocardium\u2014A Targeted Metabolomics Study","volume":"11","author":"Kim","year":"2022","journal-title":"J. Am. Heart Assoc."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Feng, S., Cai, K., Lin, S., Chen, X., Luo, Y., Wang, J., Lian, G., Lin, Z., and Xie, L. (2023). Exploring Potential Therapeutic Agents for Lipopolysaccharide-Induced Septic Cardiomyopathy Based on Transcriptomics Using Bioinformatics. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-47699-0"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Li, Y., Yu, J., Li, R., Zhou, H., and Chang, X. (2024). New Insights into the Role of Mitochondrial Metabolic Dysregulation and Immune Infiltration in Septic Cardiomyopathy by Integrated Bioinformatics Analysis and Experimental Validation. Cell. Mol. Biol. Lett., 29.","DOI":"10.1186\/s11658-024-00536-2"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1257601","DOI":"10.1126\/science.1257601","article-title":"Uncovering Disease-Disease Relationships through the Incomplete Interactome","volume":"347","author":"Menche","year":"2015","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1900","DOI":"10.1101\/gr.272484.120","article-title":"Multimodal Single-Cell\/Nucleus RNA Sequencing Data Analysis Uncovers Molecular Networks between Disease-Associated Microglia and Astrocytes with Implications for Drug Repurposing in Alzheimer\u2019s Disease","volume":"10","author":"Xu","year":"2021","journal-title":"Genome Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2691","DOI":"10.1038\/s41467-018-05116-5","article-title":"Network-Based Approach to Prediction and Population-Based Validation of in Silico Drug Repurposing","volume":"9","author":"Cheng","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3476","DOI":"10.1038\/s41467-019-10744-6","article-title":"A Genome-Wide Positioning Systems Network Algorithm for In Silico Drug Repurposing","volume":"10","author":"Cheng","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1186\/s13045-021-01214-y","article-title":"STAT Proteins: A Kaleidoscope of Canonical and Non-Canonical Functions in Immunity and Cancer","volume":"14","author":"Awasthi","year":"2021","journal-title":"J. Hematol. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"112842","DOI":"10.1016\/j.yexcr.2021.112842","article-title":"MiR-125b Enhances Autophagic Flux to Improve Septic Cardiomyopathy via Targeting STAT3\/HMGB1","volume":"409","author":"Yu","year":"2021","journal-title":"Exp. Cell Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Peng, Z., Lv, X., Wang, X., Shang, T., Chang, J., Salahdiin, K., Guo, Y., Zhang, Z., Shen, R., and Lyu, M. (2023). ACT001 Improved Cardiovascular Function in Septic Mice by Inhibiting the Production of Proinflammatory Cytokines and the Expression of JAK-STAT Signaling Pathway. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1265177"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1001\/jama.2024.8772","article-title":"Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients with Sepsis","volume":"332","author":"Ware","year":"2024","journal-title":"JAMA"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Stach, K., Stach, W., and Augoff, K. (2021). Vitamin B6 in Health and Disease. Nutrients, 13.","DOI":"10.3390\/nu13093229"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Shan, M., Yu, X., Li, Y., Fu, C., and Zhang, C. (2021). Vitamin B6 Alleviates Lipopolysaccharide-Induced Myocardial Injury by Ferroptosis and Apoptosis Regulation. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.766820"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2138","DOI":"10.1016\/j.apsb.2022.12.009","article-title":"Discovery and Identification of EIF2AK2 as a Direct Key Target of Berberine for Anti-Inflammatory Effects","volume":"13","author":"Wei","year":"2023","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"10331","DOI":"10.1038\/ncomms10331","article-title":"Network-Based In Silico Drug Efficacy Screening","volume":"7","author":"Guney","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"696897","DOI":"10.1155\/2012\/696897","article-title":"Cyclooxygenase Inhibition in Sepsis: Is There Life after Death?","volume":"2012","author":"Aronoff","year":"2012","journal-title":"Mediat. Inflamm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"R75","DOI":"10.1152\/ajpregu.00450.2013","article-title":"Role of Prostaglandins in Determining the Increased Cardiac Sympathetic Nerve Activity in Ovine Sepsis","volume":"307","author":"Booth","year":"2014","journal-title":"Am. J. Physiol.-Regul. Integr. Comp. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1002\/jimd.12060","article-title":"Disorders Affecting Vitamin B6 Metabolism","volume":"42","author":"Wilson","year":"2019","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.pharep.2016.09.021","article-title":"Diethylcarbamazine Attenuates LPS-Induced Acute Lung Injury in Mice by Apoptosis of Inflammatory Cells","volume":"69","author":"Fragoso","year":"2017","journal-title":"Pharmacol. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1038\/s41467-024-45174-6","article-title":"5-Aminosalicylic Acid Suppresses Osteoarthritis through the OSCAR-PPAR\u03b3 Axis","volume":"15","author":"Kim","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1093\/advances\/nmy054","article-title":"Nutritionally Essential Amino Acids","volume":"9","author":"Hou","year":"2018","journal-title":"Adv. Nutr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2884","DOI":"10.1002\/ehf2.12896","article-title":"Elevated Plasma Phenylalanine Predicts Mortality in Critical Patients with Heart Failure","volume":"7","author":"Chen","year":"2020","journal-title":"Esc Hear Fail"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"783730","DOI":"10.1155\/2014\/783730","article-title":"Immune Activation and Inflammation in Patients with Cardiovascular Disease Are Associated with Higher Phenylalanine to Tyrosine Ratios: The Ludwigshafen Risk and Cardiovascular Health Study","volume":"2014","author":"Murr","year":"2014","journal-title":"J. Amino Acids"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e951","DOI":"10.1002\/ctm2.951","article-title":"Single-cell Sequencing of Mouse Heart Cellular Heterogeneity in Hypercholesterolemia Reveals the Mechanism of Myocardial Damage","volume":"12","author":"Zhang","year":"2022","journal-title":"Clin. Transl. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/j.jpha.2023.02.006","article-title":"Single-Cell Transcriptome Analysis Reveals the Regulatory Effects of Artesunate on Splenic Immune Cells in Polymicrobial Sepsis","volume":"13","author":"Chen","year":"2023","journal-title":"J. Pharm. Anal."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1038\/s41596-020-0341-5","article-title":"Development of a Plasma Pseudotargeted Metabolomics Method Based on Ultra-High-Performance Liquid Chromatography\u2013Mass Spectrometry","volume":"15","author":"Zheng","year":"2020","journal-title":"Nat. Protoc."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e2025581118","DOI":"10.1073\/pnas.2025581118","article-title":"Network Medicine Framework for Identifying Drug-Repurposing Opportunities for COVID-19","volume":"118","author":"Gysi","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7421","DOI":"10.1007\/s00216-021-03699-5","article-title":"Metabolic Network-Based Identification of Plasma Markers for Non-Small Cell Lung Cancer","volume":"413","author":"Guo","year":"2021","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1007\/s00726-021-02992-y","article-title":"Attenuation of Doxorubicin-Induced Oxidative Damage in Rat Brain by Regulating Amino Acid Homeostasis with Astragali Radix","volume":"53","author":"Yu","year":"2021","journal-title":"Amino Acids"}],"updated-by":[{"DOI":"10.3390\/ph18071040","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,1,2]],"date-time":"2025-01-02T00:00:00Z","timestamp":1735776000000}}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/1\/43\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,3]],"date-time":"2025-08-03T14:45:15Z","timestamp":1754232315000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/1\/43"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,2]]},"references-count":47,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["ph18010043"],"URL":"https:\/\/doi.org\/10.3390\/ph18010043","relation":{"correction":[{"id-type":"doi","id":"10.3390\/ph18071040","asserted-by":"object"}]},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,2]]}}}