Integrated Multi-Omics and Experimental Evidence Implicates PDCD5 as a Candidate Gene Associated with Primary Biliary Cholangitis

Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disorder in which endoplasmic reticulum stress and mitochondrial dysfunction overlap with features associated with paraptosis. This study aimed to identify a paraptosis-related candidate gene for PBC via multi-omics integration and experimental validation. We integrated four transcriptomic cohorts, constructed a machine learning framework with SHAP analysis, applied two-sample Mendelian randomization (MR), and established a 2-OA-BSA/Poly I:C-induced murine PBC model. The intersection yielded eight candidate genes, and LASSO+RF modeling prioritized four core genes. Genetically predicted PDCD5 and ITPR3 expression was associated with lower PBC odds. In PBC mice, hepatic PDCD5 was downregulated alongside ER dilation, mitochondrial swelling, and stress-related molecular changes. PDCD5 overexpression in human intrahepatic biliary epithelial cells increased metabolic activity measured by CCK-8 under LPS exposure, reduced CHOP, BiP, and p-ERK/ERK, and increased ALIX. These findings nominate PDCD5 as a candidate associated with PBC and provide functional evidence that its overexpression attenuates LPS-associated cellular stress. The specific contribution of paraptosis and the requirement for ERK signaling remain to be established.