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Pharmacological induction of fetal hemoglobin (HbF) is an effective therapeutic strategy, yet existing DNA methyltransferase (DNMT) inhibitors, although effective HbF inducers, currently are not approved for \u03b2\u2010thalassemia treatment. Here, we report that DMT207, a novel non\u2010nucleoside DNMT1 inhibitor, robustly reactivates HbF in HUDEP\u20102 cells and adult primary erythroblasts with minimal toxicity. In a mouse model of \u03b2\u2010thalassemia, DMT207 effectively elevates the levels of mouse fetal\u2010 and embryonic\u2010type hemoglobin, promotes the maturation of erythroid cells, and alleviates the splenomegaly. Further multi\u2010omics analyses expose \u03b3\u2010globin as one of the most sensitive genes with promoter demethylation and transcriptional activation following DMT207 treatment. Mechanistically, DMT207 traps DNMT1 into a catalytically inactive conformation and concurrently enhances its interaction with UHRF1, which partially contributes to DNMT1 degradation. These findings highlight the therapeutic potential of DMT207 for \u03b2\u2010thalassemia and support its further preclinical development.<\/jats:p>","DOI":"10.1002\/advs.202513469","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T11:47:09Z","timestamp":1764935229000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Discovery of a Novel DNMT1 Inhibitor with Improved Efficacy in Treating \u03b2\u2010Thalassemia"],"prefix":"10.1002","volume":"13","author":[{"given":"Yijie","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Systems Biology for Medicine, School of Basic Medical Sciences, Department of Liver Surgery and Transplantation, Liver Cancer Institute Zhongshan Hospital Fudan University  130 Dong'An Road Shanghai 200032 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