Ferroptosis in hematological malignancies: molecular mechanisms and therapeutic potential.

Abstract

Ferroptosis, an iron-dependent form of regulated cell death characterized by overwhelming accumulation of lipid peroxidation, has emerged as a prominent area of interest in cancer research. Its underlying mechanisms are complex, and the high heterogeneity of hematologic malignancies adds additional challenges. Unlike solid cancers, hematologic malignancies lack fixed tissue architecture and exist within the dynamic bone marrow microenvironment, where iron metabolism, redox balance, and lipid remodeling are uniquely regulated. These differences create distinct metabolic vulnerabilities-particularly in iron and polyunsaturated fatty acid metabolism-that may render hematologic cancer cells more sensitive to ferroptotic stress. Given these unique features, a systematic understanding of ferroptosis in hematologic malignancies is critical for both elucidating disease mechanisms and exploring novel therapeutic strategies. This review summarizes the current understanding of ferroptosis in the pathogenesis and therapeutic resistance of hematologic malignancies, highlighting its mechanistic diversity across leukemia, lymphoma, and multiple myeloma. We also discuss emerging therapeutic strategies that exploit ferroptosis and outline key challenges and future directions for translating ferroptosis-based interventions into clinical practice.