Targeting STAT3-mediated lipid metabolism reprogramming overcomes chemoresistance in acute myeloid leukemia

  • Cell Death Dis. 2026 Jun 17. doi: 10.1038/s41419-026-08988-4.
Keren Peng  #  1 ,  Jianshan Mo  #  1 ,  Zhenjiao Yang  #  1 ,  Wen Ding  #  1  2 ,  Jiayu Yan  1 ,  Shumin Ouyang  1 ,  Minyuan Lu  1 ,  Kai Zhu  3 ,  Hongru Yao  4 ,  Huiqin Chen  5 ,  Xiongjun Xu  5 ,  Peibin Yue  6 ,  Jinjian Lu  7 ,  Yuanxiang Wang  1 ,  Shanyi Zhang  8 ,  Yandong Wang  9 ,  Xiaolei Zhang  10
Affiliations
  • 1. National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
  • 2. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
  • 3. Innovation Practice Center, Changchun University of Chinese Medicine, Changchun, China.
  • 4. Department of Neurosurgery, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 5. Department of Pediatrics, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 6. Department of Medicine, Division of Hematology-Oncology, and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 7. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
  • 8. Department of Neurosurgery, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. [email protected].
  • 9. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 10. National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 42310288 DOI: 10.1038/s41419-026-08988-4
Abstract

Chemotherapy resistance and intolerance present significant challenges in the effective treatment of acute myeloid leukemia (AML). However, the role of metabolic reprogramming, particularly lipid metabolic rewiring, in promoting chemotherapy resistance in leukemia has not been fully elucidated. Here, we found that multiple lipid metabolism processes are aberrantly activated in Ara-C resistant AML cells, accompanied by upregulation of JAK-STAT3 signaling and key lipid metabolic regulators, notably SREBP1 and CPT2. Additionally, we discovered W1307, a potent and highly selective STAT3 Inhibitor, which demonstrated significant anti-tumor activity both in vitro and in vivo. Genetic and pharmacological inhibition of STAT3 simultaneously suppresses lipid synthesis and catabolism, leading to lipids metabolic disorder accompanied with lipids accumulation, ROS increase, lipid peroxidation and mitochondrial membrane potential decrease. Mechanistically, STAT3 binds to DNA response elements in the promoters of the lipid metabolism associated gene SREBF1 and CPT2, and regulates their expression. Furthermore, inhibition of STAT3 enhances the anti-tumor effect of Ara-C and sensitizes resistant AML cell line to Ara-C through disrupting lipid homeostasis and triggering lipotoxicity. Our findings highlight the critical role of STAT3-driven lipid metabolism reprogramming in chemoresistance. Furthermore, W1307 emerges as a promising therapeutic candidate to overcome chemoresistance in leukemia treatment.

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