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Nonalcoholic fatty liver disease (NAFLD), characterized by hepatic triglyceride (TG) accumulation resulting from disrupted lipid homeostasis, lacks well\u2010defined epigenetic regulatory mechanisms. Here, we report that global Zfp217 heterozygous knockout alleviates high\u2010fat diet (HFD)\u2010induced hepatic steatosis in mice, as evidenced by reduced liver weight, decreased hepatic and serum TG and total cholesterol (T\u2010CHO) levels, and hepatic lipid deposition. Mechanistically, Zfp217 deficiency suppresses hepatic de novo lipogenesis (DNL) by down\u2010regulating sterol regulatory element\u2010binding transcription factor 1 (SREBF1), a master regulator of lipogenic gene expression. Zfp217 physically interacts with methyltransferase\u2010like 3 (METTL3) to repress its expression, thereby reducing m\n                    <jats:sup>6<\/jats:sup>\n                    A modification of SREBF1 mRNA at a specific coding sequence (CDS) site. Loss of Zfp217 enhances METTL3\u2010dependent m\n                    <jats:sup>6<\/jats:sup>\n                    A modification at a specific site of SREBF1 mRNA, which promotes YTH domain\u2010containing family protein 2 (YTHDF2)\u2010mediated degradation of SREBF1 transcripts. Conversely, our findings identify a novel Zfp217\u2010METTL3\u2010m\n                    <jats:sup>6<\/jats:sup>\n                    A\u2010YTHDF2\u2010SREBF1 regulatory axis that controls hepatic DNL and NAFLD progression, establishing Zfp217 as a potential therapeutic target for NAFLD.\n                  <\/jats:p>","DOI":"10.1096\/fj.202600780rr","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T16:58:42Z","timestamp":1786381122000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Zfp217 Regulates Hepatic de Novo Lipogenesis via\n                    <scp>METTL3<\/scp>\n                    \u2010Mediated\n                    <scp>N6<\/scp>\n                    \u2010Methyladenosine Modification of\n                    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Huazhong Agricultural University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nannan","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology Huazhong Agricultural University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Zheng","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology Huazhong Agricultural University  Wuhan China"},{"name":"Center for Frontier Science in Animal Breeding and Sustainable Production  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Zuo","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology Huazhong Agricultural University  Wuhan China"},{"name":"Center for Frontier Science in Animal Breeding and Sustainable Production  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanfei","family":"Zhou","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology Huazhong Agricultural University  Wuhan China"},{"name":"Center for Frontier Science in Animal Breeding and Sustainable Production  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siwen","family":"Jiang","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology Huazhong Agricultural University  Wuhan China"},{"name":"Center for Frontier Science in Animal Breeding and Sustainable Production  Wuhan 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