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This study aims to investigate the protective effects of aspirin on MASLD by incorporating transcriptomic and metabolomic approaches. Mice were fed a high\u2010fat diet (HFD) to induce MASLD and treated with aspirin for 12\u2009weeks. Blood and liver samples were collected for biochemical assays, histological analysis, RT\u2010qPCR, RNA sequencing, and non\u2010targeted metabolomics. AML12 cells were used for in\u00a0vitro experiments to validate the findings. Aspirin treatment significantly reduced plasma lipid levels and liver lipid accumulation in HFD\u2010fed mice. RNA sequencing and non\u2010targeted metabolomics identified differentially expressed genes (DEGs) and metabolites (DEMs), respectively. These findings were validated through RT\u2010qPCR for the DEGs and targeted mass spectrometry for the DEMs. Enrichment analyses highlighted several key pathways, including lipid metabolism, PPAR signaling, and bile acid metabolism. Integrated transcriptomic and metabolomic analysis identified 42 overlapped pathways that may mediate the protective effects of aspirin. In\u00a0vitro experiments confirmed that aspirin reduced lipid accumulation and inflammation in palmitic acid\u2010treated AML12 cells. Molecular docking confirmed strong binding between aspirin\/cholic acid and SULT2A3. SULT2A3 was upregulated in MASLD patients and HFD\u2010fed mice. Functional studies revealed SULT2A3 overexpression exacerbated PA\u2010induced lipid accumulation, inflammation, and bile acid dysregulation, whereas its knockdown or aspirin treatment mitigated these effects. Aspirin ameliorates MASLD by modulating SULT2A3\u2010mediated bile acid metabolism and inflammatory pathways. Sult2a3 emerges as a potential target for the treatment of MASLD.<\/jats:p>","DOI":"10.1096\/fj.202500847r","type":"journal-article","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T10:03:03Z","timestamp":1750068183000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["An Integrated Multi\u2010Omics Analysis Reveals the Protective Mechanism of Aspirin on Metabolic Dysfunction\u2010Associated Steatotic Liver Disease"],"prefix":"10.1096","volume":"39","author":[{"given":"Yanan","family":"Jiang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Laboratory\u2010Province Key Laboratories of Biomedicine\u2010Pharmaceutics of China), College of Pharmacy Harbin Medical University  Harbin China"},{"name":"Translational Medicine Research and Cooperation Center of Northern China Heilongjiang Academy of Medical Sciences  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pathophysiology, College of Basic Medical Sciences Harbin Medical University\u2010Daqing  Daqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yankun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pathophysiology, College of Basic Medical Sciences Harbin Medical University\u2010Daqing  Daqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingqi","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pathophysiology, College of Basic Medical Sciences Harbin Medical University\u2010Daqing  Daqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengnan","family":"Zhi","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pathophysiology, College of Basic Medical Sciences Harbin Medical University\u2010Daqing  Daqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoshan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pathophysiology, College of Basic Medical Sciences Harbin Medical University\u2010Daqing  Daqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiran","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pathophysiology, College of Basic Medical Sciences Harbin Medical University\u2010Daqing  Daqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengnan","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pathophysiology, College of Basic Medical Sciences Harbin Medical University\u2010Daqing  Daqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingxin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Hongqi Hospital Affiliated to Mudanjiang Medical University  Mudanjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxiao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pathophysiology, College of Basic Medical Sciences Harbin Medical University\u2010Daqing  Daqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Lin","sequence":"additional","affiliation":[{"name":"College of Pharmacy Harbin Medical University\u2010Daqing  Daqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5987-658X","authenticated-orcid":false,"given":"Yuhua","family":"Fan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Laboratory\u2010Province Key Laboratories of Biomedicine\u2010Pharmaceutics of China), College of Pharmacy Harbin Medical University  Harbin China"},{"name":"Department of Pathology and Pathophysiology, College of Basic Medical Sciences Harbin Medical University\u2010Daqing  Daqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,16]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.7861\/clinmedicine.18-3-245"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2023.07.031"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28431"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32511-3"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31173"},{"key":"e_1_2_11_7_1","article-title":"Emerging Risk Factors for Nonalcoholic Fatty Liver Disease Associated Hepatocellular Carcinoma","volume":"6","author":"Benhammou J. 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