Identifying cathepsin B as a key regulator of programmed cell death in acute pancreatitis

Acute pancreatitis (AP) lacks effective therapies, and excessive programmed cell death (PCD) drives its pathogenesis. This study identified cathepsin B (CTSB) as a core PCD regulator in AP via bioinformatics and animal experiments. Gene Expression Omnibus (GEO) datasets were analyzed with differential expression analysis, weighted gene co-expression network analysis (WGCNA), and machine learning algorithms, screening CTSB as a hub gene with high diagnostic value and enrichment in PCD/inflammatory pathways. Cerulein-induced AP mice showed activated multiple PCD pathways and elevated cytoplasmic CTSB. CTSB inhibition by CA-074 Me alleviated pancreatic inflammation and injury, reduced inflammatory cytokines, and mitigated apoptosis, restored autophagic flux, and suppressed necroptosis, ferroptosis, pyroptosis in AP tissues. CTSB is a central regulator of PCD in AP, serving as a promising therapeutic target for AP by modulating diverse PCD modalities.