RIPK1 inhibition reduces biliary injury and fibrosis in primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with no effective curative therapies. Necroptosis, a regulated necrotic cell death pathway controlled by receptor-interacting protein kinase 1 (RIPK1), has emerged as a potential driver of inflammation and fibrosis in chronic liver disorders. We investigated the role of necroptosis in PSC and whether RIPK1 inhibition could modify disease course and progression. Spatial profiling of human PSC biopsies revealed that necroptosis primarily affects cholangiocytes, while apoptosis was more frequent in hepatocytes and nonbiliary cells. In vitro, necroptosis inhibition protected cholangiocytes, and RIPK1 deletion conferred resistance to TNF-mediated cytotoxicity. In a murine model of PSC, pharmacological RIPK1 inhibition reduced cholestatic injury, hepatic inflammation, and biliary fibrosis. Multiomic analyses comprehensively demonstrated reprogramming toward wild-type-like profiles following treatment. These findings identify necroptosis as a critical effector in PSC and highlight RIPK1 inhibition as a promising disease-modifying approach, opening the door to targeted necroptosis-based therapies for this otherwise untreatable disease.