Role of Ferroptosis in AML Pathophysiology and Therapeutic Strategies

Ferroptosis, an iron-dependent form of regulated cell death marked by lipid per oxidation, is critically implicated in the pathology of acute myeloid leukemia (AML). The dysregulation of iron metabolism and ferroptotic regulators, such as GPX4, the cystine/glutamate antiporter System Xc−, and several iron homeostasis proteins, contributes to leukemic cell survival and therapy resistance. These disruptions not only facilitate the survival and proliferation of leukemic cells but also enable them to evade traditional apoptotic pathways, thereby increasing resistance to standard therapeutic interventions. Recent studies have focused on identifying specific targets within the ferroptosis pathway that are aberrantly expressed in AML, highlighting potential vulnerabilities that can be exploited for therapeutic benefit. Promising com pounds such as Erastin and RSL3 have emerged as effective inducers of ferroptosis in AML cells, demonstrating the capacity to circumvent resistance mechanisms. These agents function by inhibiting GPX4 and disrupting cystine uptake, which culminates in enhanced lipid peroxidation and cell death. This chapter explores the therapeutic potential of targeting ferroptosis in AML, with a particular focus on modulating iron metabolism and key regulatory pathways. By exploiting the vulnerabilities in fer roptotic processes, these strategies offer a novel approach to enhancing therapeutic efficacy and addressing the critical challenge of drug resistance in AML