SLC7A11/GPX4-dependent resistance to ferroptosis induction in acute myeloid leukemia cells: molecular markers and therapeutic prospects

The review presents an analysis of current literature data on the role of iron-dependent regulated cell death (ferroptosis) in the pathogenesis of acute myeloid leukemia (AML). The molecular mechanisms of SLC7A11/GPX4-dependent resistance of leukemic cells to ferroptosis induction are discussed, including transcriptional regulation of anti-ferroptotic genes by NRF2, p53, ATF4 factors, as well as epigenetic modifications. Special attention is paid to the role of leukemic stem cells in maintaining resistance through activation of alternative defense pathways (FSP1–CoQ10, DHODH) and regulation of iron homeostasis. Experimental data obtained on AML cell lines (HL-60, KG-1, MOLM-13, MV4-11, THP-1) and therapeutic strategies for pharmacological blockade of the SLC7A11–GSH–GPX4 axis using ferroptosis inducers (erastin, RSL3, ML162) are analyzed. The prospects of combination therapy with targeted drugs, hypomethylating agents, and lipid metabolism modulators are discussed. Molecular markers (SLC7A11, GPX4, ACSL4, FSP1, NRF2, lipid peroxidation level) for patient stratification and personalization of treatment for resistant forms of AML are highlighted.