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While RNA modifications are acknowledged as key regulatory elements in cancer, the role of 5\u2010methylcytosine (m\n                    <jats:sup>5<\/jats:sup>\n                    C) and its modifying enzymes in EC is still largely unstudied. Here, it demonstrates that the m\n                    <jats:sup>5<\/jats:sup>\n                    C methyltransferase NSUN6 is significantly upregulated in EC tissues, and its expression correlates with higher tumor grade and unfavorable prognosis. Functional studies employing gain\u2010 and loss\u2010of\u2010function models revealed that NSUN6 specifically enhances EC cell migration and invasion both in vitro and in vivo, without altering proliferation or apoptosis. Mechanistically, NSUN6 drives EMT by catalyzing m\n                    <jats:sup>5<\/jats:sup>\n                    C modification on Snail mRNA, which in turn stabilizes the transcript of this key EMT transcription factor. AL398\u00a0was identified through structure\u2010based virtual screening as a novel small\u2010molecule inhibitor that binds potently to the NSUN6 active site and suppresses its methyltransferase activity. Treatment with AL398 effectively inhibited the NSUN6\/m\n                    <jats:sup>5<\/jats:sup>\n                    C\/Snail axis, reversed the EMT phenotype, and attenuated EC cell migration, invasion, and metastasis in preclinical models. Collectively, it both validates the NSUN6\/m\n                    <jats:sup>5<\/jats:sup>\n                    C\/Snail axis as a critical EC vulnerability and provides a proof\u2010of\u2010concept inhibitor, AL398, laying the groundwork for the development of first\u2010in\u2010class RNA methylation\u2010targeted therapies against metastatic EC.\n                  <\/jats:p>","DOI":"10.1002\/advs.77359","type":"journal-article","created":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T06:30:50Z","timestamp":1787985050000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["AL398, A Novel NSUN6 Inhibitor, Attenuates Epithelial\u2010Mesenchymal Transition and Metastasis in Endometrial Cancer by Abrogating m5C\u2010Dependent Stabilization of Snail mRNA"],"prefix":"10.1002","author":[{"given":"Xiangzhuan","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology The Third 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