Identification of causal plasma proteins and targeted therapy for primary hepatic carcinoma via proteome-wide Mendelian randomization

Given the paucity of therapeutic targets for primary hepatic carcinoma (PHC), we performed a proteome-wide Mendelian randomization (PW-MR) analysis integrating meta-analyzed GWAS data from 816 PHC cases and 631,599 controls with two large-scale plasma proteomic datasets (deCODE and UK Biobank). Genetic instruments for 3,907 proteins were evaluated using inverse-variance weighted MR, supported by Bayesian colocalization and sensitivity analyses. This approach identified 27 circulating proteins with significant causal associations to PHC risk (false discovery rate <0.05). INHBC, a TGF-β superfamily ligand, emerged as the top pathogenic candidate, and mechanistic experiments revealed that it activates ACVR2B–Smad2 signaling to drive hepatocellular carcinoma cell proliferation and invasion. Importantly, ACVR2B blockade with Bimagrumab—a clinical-stage antibody—suppressed INHBC-driven tumor growth in a mouse xenograft model (~42% tumor volume reduction vs. controls, P = 0.008). Cross-phenotype analyses linked PHC genetically to metabolic liver diseases, and Bayesian colocalization confirmed shared causal variants at the NCAN locus (PPH4 = 0.782). Complementary druggability profiling prioritized ACVR2B and C1QA as actionable targets. These findings establish the INHBC–ACVR2B axis as a validated pathogenic mechanism in PHC and underscore the potential of repurposing ACVR2B inhibitors (e.g., Bimagrumab) as a precision oncology strategy for PHC management.