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Although N6\u2010methyladenosine (m6A) RNA methylation has been implicated in hepatic pathophysiology, its role in PSC remains undefined. Here, we demonstrate that hepatocyte\u2010specific deletion of\n                    <jats:italic>Mettl3<\/jats:italic>\n                    , a critical m6A methyltransferase, induces spontaneous PSC\u2010like pathology characterized by ductular reaction and peribiliary fibrosis. Therapeutic restoration of\n                    <jats:italic>Mettl3<\/jats:italic>\n                    through genetic knock\u2010in or AAV8\u2010mediated hepatocyte\u2010specific overexpression significantly attenuated 3,5\u2010diethoxycarbonyl\u20101,4\u2010dihydrocollidine (DDC)\u2010induced PSC progression. Integrated single\u2010cell and bulk transcriptomic profiles revealed an expansion of Trem2\n                    <jats:sup>+<\/jats:sup>\n                    macrophages that interact with Spp1\n                    <jats:sup>high<\/jats:sup>\n                    cholangiocytes via the Cd44\u2010Spp1 axis. Genetic ablation of\n                    <jats:italic>Trem2<\/jats:italic>\n                    or cholangiocyte\u2010specific deletion of\n                    <jats:italic>Spp1<\/jats:italic>\n                    significantly suppressed DDC\u2010induced biliary injury. Mechanistically,\n                    <jats:italic>Mettl3<\/jats:italic>\n                    \u2010deficient hepatocytes secreted higher levels of macrophage\u2010recruiting cytokines (such as Mif and Csf1), facilitating the recruitment of Trem2\n                    <jats:sup>+<\/jats:sup>\n                    macrophage, which subsequently activated cholangiocytes through Cd44\u2010Spp1 signaling, exacerbated biliary inflammation and fibrosis. Notably, pharmacological activation of Mettl3 in adult hepatocytes substantially mitigated PSC progression and liver fibrosis. Collectively, our findings establish hepatocyte\n                    <jats:italic>Mettl3<\/jats:italic>\n                    deficiency as a pivotal driver of PSC pathogenesis and highlight the therapeutic potential of targeting the m6A epitranscriptome in cholestatic liver diseases.\n                  <\/jats:p>","DOI":"10.1002\/advs.202512799","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T06:15:00Z","timestamp":1766470500000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Hepatocyte Mettl3 Deficiency Drives Primary Sclerosing Cholangitis and Liver Fibrosis via Cholangiocyte\u2010Macrophage Crosstalk"],"prefix":"10.1002","volume":"13","author":[{"given":"Wenting","family":"Pan","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Environmental and Viral Oncology College of Chemistry and Life Science Beijing University of Technology  Beijing 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