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

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.