Integrative Mendelian randomization and experimental validation unveil novel druggable targets in primary biliary...

Primary Biliary Cholangitis (PBC) is a progressive autoimmune liver disorder characterized by immune-mediated bile duct destruction, leading to cirrhosis and liver failure. Current first-line therapy with ursodeoxycholic acid (UDCA) exhibits suboptimal efficacy in 30-40% of patients, underscoring the urgent need for novel therapeutic targets.

We employed a druggable genome-wide Mendelian randomization (MR) framework integrating blood/liver cis-eQTLs, pQTLs, and PBC GWAS meta-analysis. Bayesian colocalization and phenome-wide MR (Phe-MR) validated causal relationships and off-target effects. Protein-protein interaction (PPI) networks and transcriptomic profiling elucidated biological mechanisms. Drug repurposing via DSigDB and molecular docking prioritized compounds, with efficacy validated in ANIT-induced cholestasis models and human PBC biopsies.

MR analysis identified 14 druggable genes causally associated with PBC risk, with replication in the FinnGen cohort confirming CD58 and IL7R as tier-1 targets. Functional studies revealed both genes modulate immune synapse formation and T-cell homeostasis, supported by significant hepatic overexpression in human PBC biopsies. Molecular docking prioritized PHA-00665752 and monorden as high-affinity binders. In vivo validation demonstrated that PHA-00665752 significantly attenuated ANIT-induced cholestasis.

This study establishes CD58 and IL7R as mechanistically grounded therapeutic targets for PBC. We provide a translational framework integrating causal genomics, computational drug screening, and experimental validation by demonstrating their protective effects against cholestatic bile duct injury, thereby informing therapy development for PBC.