Ferroptosis in chronic myeloid leukemia and its roles in treatment resistance and treatment related complications

Ferroptosis, an iron-dependent programmed cell death mechanism driven by lipid peroxidation, has emerged as a potentially relevant mechanism in cancer biology, including chronic myeloid leukemia (CML), a hematopoietic stem cell disorder characterized by the BCR-ABL1 oncogene. This review consolidates current evidence regarding the possible role of ferroptosis in the pathophysiology and treatment of CML, with particular attention to treatment resistance, including tyrosine kinase inhibitor (TKI) resistance, and treatment toxicity. Available studies suggest that the SLC7A11/GSH/GPX4, NRF2, and thioredoxin pathways may be involved in the regulation of ferroptosis in CML cell lines (e.g., K562, KBM5), with compounds such as hesperadin, disulfiram, and hyperoside reported to induce ferroptosis in experimental CML models. Preclinical findings further suggest that pharmacological modulation of ferroptosis may enhance TKI sensitivity in resistant CML cells, including through agents such as erastin and RSL3. Ferroptosis-related gene signatures have also been investigated for their possible association with disease-related characteristics, while experimental evidence suggests that modulation of ferroptosis may influence imatinib-associated cardiotoxicity, including in studies involving berberine. Although there are fewer studies on CML compared to other malignancies, emerging preclinical findings indicate that ferroptosis-related pathways may represent a potential therapeutic vulnerability in CML.