ALDH3A2-mediated fatty acid synthesis induces ferroptosis and AML drug resistance

  • iScience. 2026 Jun 2;29(6):116202. doi: 10.1016/j.isci.2026.116202.
Yun Huang  1 ,  Yu Zhao  2 ,  Ping Yan  1 ,  Zhiquan Long  1 ,  Chuang Xia  3 ,  Ling Jiang  1 ,  Yujiao Zhang  1 ,  Jiaying Cheng  1 ,  Fang Liu  1 ,  Quan Wu  1 ,  Zhongzhen Zhou  3 ,  Xuejie Jiang  1
Affiliations
  • 1. Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
  • 2. Department of Hematology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510515, China.
  • 3. Innovation Program of Drug Research on Neurological and Metabolic Diseases, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
PMID: 42291184 DOI: 10.1016/j.isci.2026.116202
Abstract

Chemoresistance in acute myeloid leukemia (AML) is associated with a poor prognosis in patients. Ferroptosis is one of the mechanisms by which anthracycline exerts anti-leukemic effects, with drug-resistant AML cells exhibiting increased resistance to Ferroptosis. Elevated expression of aldehyde dehydrogenase 3 family member A2 (ALDH3A2) is correlated with poor prognosis in patients with AML. Patients with chemo-resistant AML exhibit higher levels of ALDH3A2, particularly the V subtype. ALDH3A2 degraded 4-hydroxynonenal and regulated the fatty acid proportion and content of AML cells, protecting AML cells against doxorubicin-induced Ferroptosis. Moreover, overexpression of ALDH3A2 changes cell membrane fluidity and reduces drug uptake. Histone deacetylase 2 binds to the ALDH3A2 promoter and regulates its expression. The inhibition of ALDH3A2 or HDAC enhances chemotherapeutic efficacy in AML.

Keywords
Cancer; Molecular network; Therapeutics.
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