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Exploring the molecular mechanisms underlying disease progression holds significant promise for improving clinical outcomes. In this investigation, utilizing single-cell transcriptome sequencing technology, we discerned a correlation between Ubiquitin-like containing PHD and RING finger domain 1 (\n                    <jats:italic>UHRF1<\/jats:italic>\n                    ) and the progression of B-cell acute lymphoblastic leukemia. Our findings reveal a significant upregulation of UHRF1 in cases of relapsed and refractory B-cell acute lymphoblastic leukemia, thereby serving as a prognostic indicator for poor outcomes. Both deletion of\n                    <jats:italic>UHRF1<\/jats:italic>\n                    or overexpression of its downstream target secreted frizzled-related protein 5 (\n                    <jats:italic>SFRP5<\/jats:italic>\n                    ) resulted in the inhibition of leukemia cell proliferation, promoting cellular apoptosis and induction of cell cycle arrest. Our results showed that\n                    <jats:italic>UHRF1<\/jats:italic>\n                    employs methylation modifications to repress the expression of\n                    <jats:italic>SFRP5<\/jats:italic>\n                    , consequently inducing the WNT5A-P38 MAPK-HK2 signaling axis, resulting in the augmentation of lactate, the critical metabolic product of aerobic glycolysis. Furthermore, we identified UM164 as a targeted inhibitor of\n                    <jats:italic>UHRF1<\/jats:italic>\n                    that substantially inhibits P38 protein phosphorylation, downregulates\n                    <jats:italic>HK2<\/jats:italic>\n                    expression, and reduces lactate production. UM164 also demonstrated antileukemic activity both in vitro and in vivo. In summary, our investigation revealed the molecular mechanisms of epigenetic and metabolic reprogramming in relapsed and refractory B-cell acute lymphoblastic leukemia and provides potential targeted therapeutic strategies to improve its inadequate prognosis.\n                  <\/jats:p>","DOI":"10.1038\/s41419-025-07532-0","type":"journal-article","created":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T02:25:07Z","timestamp":1745893507000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["UHRF1-mediated epigenetic reprogramming regulates glycolysis to promote progression of B-cell acute lymphoblastic leukemia"],"prefix":"10.1038","volume":"16","author":[{"given":"Yan","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luting","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangqi","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiazheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengjun","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxing","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peifang","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haojie","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingyan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5230-571X","authenticated-orcid":false,"given":"Yanxin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6604-8937","authenticated-orcid":false,"given":"Ting","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4438-2544","authenticated-orcid":false,"given":"Jianda","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,29]]},"reference":[{"key":"7532_CR1","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/s13045-021-01060-y","volume":"14","author":"Z Hong","year":"2021","unstructured":"Hong Z, Wei Z, Xie T, Fu L, Sun J, Zhou F, et al. 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