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Consequently, the identification of therapeutic targets to reverse lenvatinib resistance may offer novel strategies to achieve enhanced and durable treatment responses. In this study, a global elevation in the levels of m5C modification is observed in lenvatinib\u2010resistant cells compared with their parental counterparts. DNA methyltransferase 2(DNMT2), functioning as an RNA methyltransferase, is markedly upregulated in lenvatinib\u2010resistant specimens and correlated with poor patient survival outcomes. Both in vitro and in vivo experiments indicated that DNMT2 downregulation effectively overcame lenvatinib resistance by reducing HCC cell proliferation and promoting apoptosis, thereby restoring drug sensitivity. Mechanistically, DNMT2 functioned together with Y\u2010box binding protein 1 (YBX1) to stabilize downstream adenosine triphosphate citrate lyase (ACLY) mRNA through m5C modification. This process activated the Notch signaling pathway by increasing intracellular acetyl\u2010CoA levels and promoting histone acetylation, driving the progression of lenvatinib resistance. Critically, pharmacological inhibition of ACLY combined with lenvatinib treatment enhanced the therapeutic efficacy against HCC and could reduce the tumor burden in multiple preclinical models. Collectively, the findings indicate the importance of the DNMT2\u2010ACLY\u2010NOTCH signaling axis in lenvatinib resistance and propose novel combinatorial therapies to improve HCC treatment outcomes.<\/jats:p>","DOI":"10.1002\/advs.202515931","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T17:10:49Z","timestamp":1766164249000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["DNMT2\u2010m5C\u2010ACLY Axis Promotes Lenvatinib Resistance in Hepatocellular Carcinoma Through Histone Acetylation\u2010Mediated Notch Pathway"],"prefix":"10.1002","volume":"13","author":[{"given":"Shiguang","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary Surgery and Liver Transplantation Key Laboratory of Carcinogenesis and Cancer Invasion Liver Cancer Institute Zhongshan Hospital Fudan University  Shanghai China"},{"name":"Department of Hepatobiliary and 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