Ferroptosis regulation and acute leukemia: Mechanisms and therapeutic perspectives

Acute leukemia is a highly malignant hematologic neoplasm. The therapeutic efficacy of current regimens remains limited, particularly due to the development of chemotherapy resistance and disease relapse, underscoring the urgent need for novel strategies. Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. It operates independently of the apoptotic pathway and directly targets the metabolic vulnerabilities of leukemia cells, such as their iron dependency and high ROS state. This mechanism directly addresses the issue of apoptosis resistance. This review elucidates the core regulatory mechanisms of ferroptosis and specifically investigates its distinct roles in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Research in AML and ALL has demonstrated a dynamic balance between pro- and anti-ferroptosis pathways, which confers heightened susceptibility to ferroptosis inducers in these malignancies. Pharmacological targeting of key regulators such as SLC7A11, GPX4, and ROS effectively triggers ferroptosis and synergizes with conventional chemotherapeutic agents to augment anti-leukemic efficacy, as demonstrated by compelling preclinical evidence. Integrated analysis of multi-omics cohorts in this study revealed marked activation of the ferroptosis pathway in AML, particularly enriched in chemotherapy-resistant samples. These findings suggest that ferroptosis inducers hold promise as a potential adjunctive therapeutic strategy. Moreover, this study highlights the clinical translational potential of targeting ferroptosis in acute leukemia treatment, while also underscoring the need for further mechanistic investigations and the development of highly efficient and low-toxicity ferroptosis-inducing agents.