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<p>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.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月17日

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  • Keren Peng,
  • Jianshan Mo,
  • Zhenjiao Yang,
  • Wen Ding,
  • Jiayu Yan,
  • Shumin Ouyang,
  • Minyuan Lu,
  • Kai Zhu,
  • Hongru Yao,
  • Huiqin Chen,
  • Xiongjun Xu,
  • Peibin Yue,
  • Jinjian Lu,
  • Yuanxiang Wang,
  • Shanyi Zhang,
  • Yandong Wang,
  • Xiaolei Zhang

摘要

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.