Rethinking Pathogenesis of Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive fibroinflammatory injury of intrahepatic and extrahepatic bile ducts that may lead to cirrhosis, hepatobiliary malignancy, and death, with liver transplantation representing the only effective intervention in end-stage disease. Rather than a single dominant pathomechanism, the data support a model in which four axes - bile acid metabolism, the intestinal microbiome and gut barrier, biliary epithelial dysfunction, and Th17-skewed immune dysregulation - are reciprocally coupled and converge on a shared periductal fibrogenic output dominated by TGF-beta signaling. This review summarizes key mechanistic advances from genetic, epigenomic, single-cell, spatial transcriptomic, and microbiome studies. These investigations implicate antigen presentation pathways, Th17-skewed immune responses, cholangiocyte senescence and profibrotic signaling, and disrupted gut-liver communication as central drivers of chronic biliary injury. Emerging spatial and multi-omics approaches further reveal complex cellular crosstalk among cholangiocytes, immune cells, macrophages, and mesenchymal populations within portal inflammatory niches. We discuss evolving biomarkers and recent clinical trial data targeting bile acid metabolism, fibrosis, the microbiome, and immune pathways. In conclusion, research data suggests viewing PSC as a network disease, which provides a unifying framework for disease pathogenesis and may enable biomarker-guided patient stratification and mechanism-based therapy development targeting distinct pathogenic pathways.