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Methylation of histone is an important epigenetic mechanism, but it is unclear whether histone methyltransferases are potent targets for fibrosis\u2010associated HCC therapy. ASH1L, an H3K4 methyltransferase, is found at higher levels in activated hepatic stellate cells (HSCs) and hepatoma cells. To determine the role of ASH1L in vivo, transgenic mice with conditional\n                    <jats:italic>Ash1l<\/jats:italic>\n                    depletion in the hepatocyte cell lineage (\n                    <jats:italic>\n                      Ash1l\n                      <jats:sup>flox\/flox<\/jats:sup>\n                      Alb\n                      <jats:sup>cre<\/jats:sup>\n                    <\/jats:italic>\n                    ) or HSCs (\n                    <jats:italic>\n                      Ash1l\n                      <jats:sup>flox\/flox<\/jats:sup>\n                      GFAP\n                      <jats:sup>creERT2<\/jats:sup>\n                    <\/jats:italic>\n                    ) are generated, and these mice are challenged in a diethylnitrosamine (DEN)\/carbon tetrachloride (CCl\n                    <jats:sub>4<\/jats:sub>\n                    )\u2010induced model of liver fibrosis and HCC. Depleting\n                    <jats:italic>Ash1l<\/jats:italic>\n                    in both hepatocytes and HSCs mitigates hepatic fibrosis and HCC development. Multicolor flow cytometry, bulk, and single\u2010cell transcriptomic sequencing reveal that ASH1L creates an immunosuppressive microenvironment. Mechanically, ASH1L\u2010mediated H3K4me3 modification increases the expression of CCL2 and CSF1, which recruites and polarizes M2\u2010like pro\u2010tumorigenic macrophages. The M2\u2010like macrophages further enhance tumor cell proliferation and suppress CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell activation. AS\u201099, a small molecule inhibitor of ASH1L, demonstrates similar anti\u2010fibrosis and tumor\u2010suppressive effects. Of pathophysiological significance, the increased expression levels of mesenchymal ASH1L and M2 marker CD68 are associated with poor prognosis of HCC. The findings reveal ASH1L as a potential small\u2010molecule therapeutic target against fibrosis\u2010related HCC.\n                  <\/jats:p>","DOI":"10.1002\/advs.202404756","type":"journal-article","created":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T13:04:55Z","timestamp":1728392695000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["ASH1L in Hepatoma Cells and Hepatic Stellate Cells Promotes Fibrosis\u2010Associated Hepatocellular Carcinoma by Modulating Tumor\u2010Associated Macrophages"],"prefix":"10.1002","volume":"11","author":[{"given":"Yuyang","family":"Du","sequence":"first","affiliation":[{"name":"Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology  Shenzhen 518055 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shasha","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology  Shenzhen 518055 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoyan","family":"Xi","sequence":"additional","affiliation":[{"name":"Department of Pathology Sun Yat\u2010Sen University Cancer Center  Guangzhou 510275 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Xu","sequence":"additional","affiliation":[{"name":"GMU\u2010GIBH Joint School of Life Sciences, The Guangdong\u2010Hong Kong\u2010Macau Joint Laboratory for Cell Fate Regulation and Diseases Guangzhou Medical University  Guangzhou 511436 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangzhan","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology  Shenzhen 518055 China"},{"name":"Department of Clinical Oncology The University of Hong Kong  Hong Kong 999077 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University  Shenzhen 518000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fenfen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology  Shenzhen 518055 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology  Shenzhen 518055 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Xie","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine Sun Yat\u2010sen University Cancer Center  Guangzhou 510080 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