Targeting STAT3-Mediated Lipid Metabolism Reprogramming Overcomes Chemoresistance in Acute Myeloid Leukemia

Among the distinctive features associated with chemoresistance, metabolic reprogramming emerges as a key factor. In this study, we unveil a novel mechanism contributing to chemoresistance in leukemia, specifically highlighting the pivotal role of altered lipid homeostasis.We found that multiple lipid metabolism processes are aberrantly activated in Ara-C resistant AML cells, with upregulation of JAK-STAT3 signaling pathways and multiple enzymes in the process of fatty acid metabolism.

A potent, and highly selective STAT3 inhibitor, W1307, was designed, and exhibited significant anti-tumor activities in vitro and in vivo. Genetic and pharmacological inhibition of STAT3 leads to inhibition of lipid synthesis and catabolism, resulting lipids metabolic disorder. Mechanistically, STAT3 binds to consensus DNA response elements in the promoters of the lipid metabolism associated genes (SREBP1, CPT2) and regulates their expression.