Integrative multi-omics and causal inference unveil novel therapeutic targets for primary sclerosing cholangitis and its genetic comorbidity with inflammatory bowel disease

Abstract Primary sclerosing cholangitis (PSC), a progressive liver disease with limited treatment options, exhibits frequent comorbidity with inflammatory bowel disease (IBD), yet shared therapeutic targets remain unexplored. Leveraging integrative multi-omics approaches—including transcriptome-wide association studies (TWAS), Mendelian randomization (MR), methylation-based MR (mMR), and colocalization—we identified three novel druggable targets for PSC: COL7A1, ABCB9, and TRIM10. Single-cell RNA sequencing revealed cell type-specific dysregulation of these targets, and molecular docking prioritized six medications (e.g., Larsucosterol, Cilofexor) with strong binding affinities. Bidirectional genetic causality between PSC and IBD was observed via MR, while mMR suggested inhibitory effects of PSC on IBD progression. COL7A1 emerged as a potential co-target, demonstrating stable mediation across both diseases. These findings advance PSC drug discovery, elucidate mechanisms underlying PSC-IBD comorbidity, and propose dual therapeutic strategies. Integrating causal inference with multi-omics data offers a translational framework for targeting immune-mediated diseases, bridging gaps in hepatobiliary and gastrointestinal therapeutics.