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

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.