2. Academic Validation
  3. Marrow leptin-LEPR signaling rewires mitochondrial oxidative metabolism to confer chemoresistance in acute myeloid leukemia

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

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.

Figures
Products