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

  • Eur J Pharmacol. 2026 Apr 10:1020:178775. doi: 10.1016/j.ejphar.2026.178775.
Yinling Li  1 ,  Huanhuan Xie  2 ,  Zhenjie Zhuang  2 ,  Xin Fang  3 ,  Wenjun Yang  4 ,  Yan Luo  5 ,  Jiangyi Hu  2 ,  Wei Wang  2 ,  Haitao Wang  6 ,  Xiaobing Dou  7 ,  Junping Shi  8 ,  Jin Yang  9
Affiliations
  • 1. Department of Translational Medicine Center, Hangzhou Normal University Affiliated Hospital, Hangzhou, Zhejiang, China; Institute of Hepatology and Metabolic Diseases, Hangzhou Normal University, Hangzhou, Zhejiang, China; Department of School of Life Sciences, Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310053, China.
  • 2. Department of Translational Medicine Center, Hangzhou Normal University Affiliated Hospital, Hangzhou, Zhejiang, China; Institute of Hepatology and Metabolic Diseases, Hangzhou Normal University, Hangzhou, Zhejiang, China.
  • 3. Department of Translational Medicine Center, Hangzhou Normal University Affiliated Hospital, Hangzhou, Zhejiang, China.
  • 4. Department of Pathology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China.
  • 5. Institute of Hepatology and Metabolic Diseases, Hangzhou Normal University, Hangzhou, Zhejiang, China.
  • 6. William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
  • 7. Department of School of Life Sciences, Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310053, China; Zhejiang-Hong Kong Joint Laboratory of Liver and Spleen Simultaneous Treatment in Traditional Chinese Medicine, Zhejiang, 310053, China.
  • 8. Institute of Hepatology and Metabolic Diseases, Hangzhou Normal University, Hangzhou, Zhejiang, China; Department of Liver Disease, Hangzhou Normal University Affiliated Hospital, Hangzhou, Zhejiang, China. Electronic address: [email protected].
  • 9. Department of Translational Medicine Center, Hangzhou Normal University Affiliated Hospital, Hangzhou, Zhejiang, China; Institute of Hepatology and Metabolic Diseases, Hangzhou Normal University, Hangzhou, Zhejiang, China. Electronic address: [email protected].
PMID: 41819524 DOI: 10.1016/j.ejphar.2026.178775
Abstract

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.

Keywords
Cholestasis; Colocalization; Druggable genes; Mendelian randomization; Primary biliary cholangitis.
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