Integrated Multi‐Omics Analysis and Experimental Validation Identify BCAT1 as a Critical Driver of Hepatocyte Pyroptosis in Acute‐On‐Chronic Liver Failure

Acute‐on‐chronic liver failure (ACLF) is characterized by profound metabolic dysfunction and high mortality. Identifying amino acid metabolism‐related biomarkers is crucial for early diagnosis and therapeutic intervention. Amino acid metabolism‐related genes (AAMGs) and ACLF transcriptomic data were integrated to identify core genes via weighted gene co‐expression network analysis (WGCNA) and differential expression analysis. Three machine learning (ML) algorithms—Random Forest, SVM‐RFE, and Boruta—were applied to screen hub genes. Specific cellular profiles and immune landscapes were characterized using single‐cell RNA sequencing (scRNA‐seq) and ssGSEA. The pathological role of BCAT1 was investigated in APAP‐induced ACLF models. A total of 26 genes were identified at the intersection of module genes, DEGs, and AAMGs. ML confirmed a three‐gene signature (BCAT1, RPS6, OAT) with high diagnostic accuracy. ScRNA‐seq analysis further verified that BCAT1 is predominantly expressed in hepatocytes, indicating its cell‐type specific role in liver injury progression. In vitro and in vivo experiments demonstrated that BCAT1 exacerbates hepatocyte injury by activating the GSDMD/Caspase‐1‐mediated pyroptosis pathway. Our study reveals that BCAT1 is a pivotal driver of hepatocyte pyroptosis in ACLF. Targeting the BCAT1‐mediated metabolic‐inflammatory axis offers a promising therapeutic strategy for managing ACLF.