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Here, we report that elevated bone-marrow leptin and blast-cell leptin-receptor (LEPR) levels strongly associate with poor cytarabine (Ara-C) clearance and reduced survival in newly diagnosed AML patients. Mechanistic and functional validation in human AML lines, primary blasts, and two syngeneic mouse models (MLL-AF9, AML1-ETO9a) shows that exogenous leptin markedly blunts Ara-C cytotoxicity, whereas the high-affinity LEPR antagonist Allo-aca restores chemosensitivity without altering baseline leukemia growth. Leptin up-regulates LEPR and triggers JAK2\/STAT3 signaling that boosts mitochondrial complex \u2160 activity, oxidative phosphorylation, and mitochondrial reactive oxygen species (mtROS); the resulting mtROS surge activates a compensatory antioxidant program that shields blasts from drug-induced oxidative damage. These data identify an adipokine-driven metabolic circuit governing AML chemoresistance and reveal LEPR blockade as a tractable strategy to improve outcomes, underscoring adipose\u2013tumor crosstalk as a general therapeutic vulnerability.<\/jats:p>","DOI":"10.1038\/s41419-026-08528-0","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T07:05:03Z","timestamp":1771830303000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Marrow leptin-LEPR signaling rewires mitochondrial oxidative metabolism to confer chemoresistance in acute myeloid leukemia"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5886-336X","authenticated-orcid":false,"given":"Xinai","family":"Liao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2345-7454","authenticated-orcid":false,"given":"Xiaolin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9254-1207","authenticated-orcid":false,"given":"Danni","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6185-9439","authenticated-orcid":false,"given":"Maoqing","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5274-6531","authenticated-orcid":false,"given":"Zukai","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3652-6741","authenticated-orcid":false,"given":"Yanrong","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8561-7424","authenticated-orcid":false,"given":"Diyu","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5626-1216","authenticated-orcid":false,"given":"Jingru","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9122-4143","authenticated-orcid":false,"given":"Liuhuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1031-6968","authenticated-orcid":false,"given":"Xiaoting","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0649-5556","authenticated-orcid":false,"given":"Shuxia","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4583-8118","authenticated-orcid":false,"given":"Xinjian","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8548-028X","authenticated-orcid":false,"given":"Huifang","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,23]]},"reference":[{"key":"8528_CR1","doi-asserted-by":"publisher","first-page":"n2026","DOI":"10.1136\/bmj.n2026","volume":"375","author":"LF Newell","year":"2021","unstructured":"Newell LF, Cook RJ. 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