Hepatocyte Mettl3 Deficiency Drives Primary Sclerosing Cholangitis and Liver Fibrosis via Cholangiocyte-Macrophage Crosstalk.

Adv Sci (Weinh) 2026

Pan W, Yong Y, Li Y, Shi G, Zhang M et al.

Abstract

Effective therapies for primary sclerosing cholangitis (PSC), a progressive cholestatic liver disease characterized by biliary inflammation and fibrotic damage, remain limited due to an incomplete elucidation of its underlying molecular mechanisms. Although N6-methyladenosine (m6A) RNA methylation has been implicated in hepatic pathophysiology, its role in PSC remains undefined. Here, we demonstrate that hepatocyte-specific deletion of Mettl3, a critical m6A methyltransferase, induces spontaneous PSC-like pathology characterized by ductular reaction and peribiliary fibrosis. Therapeutic restoration of Mettl3 through genetic knock-in or AAV8-mediated hepatocyte-specific overexpression significantly attenuated 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced PSC progression. Integrated single-cell and bulk transcriptomic profiles revealed an expansion of Trem2

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