Marrow leptin-LEPR signaling rewires mitochondrial oxidative metabolism to confer chemoresistance in acute myeloid leukemia

  • Cell Death Dis. 2026 Feb 23;17(1):249. doi: 10.1038/s41419-026-08528-0.
Xinai Liao  #  1 ,  Wei Dai  #  1 ,  Xiaolin Xu  1 ,  Danni Cai  1 ,  Maoqing Tan  1 ,  Zukai Wang  2 ,  Yanrong Huang  1 ,  Diyu Hou  1 ,  Jingru Liu  1 ,  Liuhuan Wang  1 ,  Jin Wang  1 ,  Xiaoting Wang  1 ,  Shuxia Zhang  3 ,  Xinjian Lin  4 ,  Huifang Huang  5
Affiliations
  • 1. Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, Fujian, 350001, China.
  • 2. Department of Colorectal Surgery, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, 350005, China.
  • 3. Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, Fujian, 350001, China.
  • 4. Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, Fujian, 350122, China. [email protected].
  • 5. Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, Fujian, 350001, China. [email protected].
  • # Contributed equally.
PMID: 41730833 DOI: 10.1038/s41419-026-08528-0
Abstract

Leptin is abundant within marrow adipose tissue, yet its impact on acute myeloid leukemia (AML) therapy response is undefined. 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 Ⅰ 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-tumor crosstalk as a general therapeutic vulnerability.

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