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Identifying amino acid metabolism\u2010related biomarkers is crucial for early diagnosis and therapeutic intervention. Amino acid metabolism\u2010related genes (AAMGs) and ACLF transcriptomic data were integrated to identify core genes via weighted gene co\u2010expression network analysis (WGCNA) and differential expression analysis. Three machine learning (ML) algorithms\u2014Random Forest, SVM\u2010RFE, and Boruta\u2014were applied to screen hub genes. Specific cellular profiles and immune landscapes were characterized using single\u2010cell RNA sequencing (scRNA\u2010seq) and ssGSEA. The pathological role of BCAT1 was investigated in APAP\u2010induced ACLF models. A total of 26 genes were identified at the intersection of module genes, DEGs, and AAMGs. ML confirmed a three\u2010gene signature (BCAT1, RPS6, OAT) with high diagnostic accuracy. ScRNA\u2010seq analysis further verified that BCAT1 is predominantly expressed in hepatocytes, indicating its cell\u2010type specific role in liver injury progression. In\u00a0vitro and in\u00a0vivo experiments demonstrated that BCAT1 exacerbates hepatocyte injury by activating the GSDMD\/Caspase\u20101\u2010mediated pyroptosis pathway. Our study reveals that BCAT1 is a pivotal driver of hepatocyte pyroptosis in ACLF. Targeting the BCAT1\u2010mediated metabolic\u2010inflammatory axis offers a promising therapeutic strategy for managing ACLF.<\/jats:p>","DOI":"10.1096\/fj.202600199rr","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T15:39:44Z","timestamp":1780933184000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated Multi\u2010Omics Analysis and Experimental Validation Identify BCAT1 as a Critical Driver of Hepatocyte Pyroptosis in Acute\u2010On\u2010Chronic Liver Failure"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-6896-7533","authenticated-orcid":false,"given":"Mengyue","family":"Li","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary Surgery The Third Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"},{"name":"Department of Gastroenterology Zhujiang Hospital of Southern Medical University  Guangzhou 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