2. Academic Validation
  3. IDH1 mutation creates a dependency on fatty acid metabolism that underlies sensitivity to cuproptosis in acute myeloid leukemia cells

IDH1 mutation creates a dependency on fatty acid metabolism that underlies sensitivity to cuproptosis in acute myeloid leukemia cells

  • Int J Med Sci. 2026 Feb 26;23(4):1243-1256. doi: 10.7150/ijms.127886.
Xuening Zhang 1 2 3,  Dayuan Zheng 1 2,  Tong Chu 1 2,  Dongfan Yang 1 2,  Kuanyun Zhang 1 2,  Shaokui Liang 1 2,  Lu Yang 1 2,  Wenzhe Ma 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Mechanism and Quality of Chinese Medicine & School of Pharmacy, Faculty of Medicine, Macau University of Science and Technology, Macau SAR 999078, China.
  • 2 Zhuhai MUST Science and Technology Research Institute, Macau University of Science and Technology, Hengqin Guangdong-Macao In-Depth Cooperation Zone, Guangdong, 519099, China.
  • 3 Department of Hematology, The Third Affiliated Hospital, Sun Yat-sen University; Institute of Hematology, Sun Yat-sen University, Guangzhou, China.
PMID: 41938504 DOI: 10.7150/ijms.127886
Abstract

Acute myeloid leukemia (AML) harboring IDH1 mutations presents unique metabolic vulnerabilities that remain incompletely addressed by current targeted therapies. In this study, we demonstrate that IDH1-mutant AML cells are markedly more sensitive to Cuproptosis induced by the copper ionophore elesclomol (ES), compared to their wild-type counterparts. While ES impairs mitochondrial function in both cell types, transcriptomic profiling reveals that ES treatment induces a global downregulation of lipid metabolism pathways. Functional assays further show that IDH1-mutant cells rely more heavily on exogenous fatty acids and exhibit impaired de novo lipogenesis. Under lipid-deprived conditions, ES-induced cytotoxicity is significantly enhanced, suggesting a synthetic-lethal interaction between Cuproptosis and fatty acid metabolic deficiency. In vivo experiments confirm that ES more effectively suppresses tumor growth in IDH1-mutant xenografts. These findings uncover a copper-dependent metabolic vulnerability and provide a rationale for exploiting Cuproptosis as a therapeutic strategy in IDH1-mutant AML.

Keywords

acute myeloid leukemia; cuproptosis; fatty acid; isocitrate dehydrogenase 1 mutation.

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