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.