Ali Dehghanifard

Acute myeloid leukemia (AML) remains a formidable clinical challenge due to high relapse rates and therapeutic resistance. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, glutathione depletion, and Glutathione peroxidase 4 (GPX4) inactivation, has emerged as a promising strategy to overcome apoptosis evasion in AML. This review synthesizes recent advances in ferroptosis biology within AML, highlighting the unique metabolic vulnerabilities of leukemic cells, including dysregulated iron homeostasis, elevated reactive oxygen species (ROS), and cystine/glutamine dependencies, that create a “ferroptotic trap.” Despite promising preclinical outcomes, challenges such as biomarker validation, metabolic evasion, and nanoparticle delivery optimization persist. By addressing these hurdles, ferroptosis induction represents a transformative paradigm for next-generation AML therapeutics, offering novel avenues to eradicate resistant clones and rewire immunosuppressive niches. We explore cutting-edge pharmacological inducers (e.g., erastin, APR-246) and nanoparticle-based technologies (e.g., ferumoxytol, FAST nanoparticles) that enhance tumor selectivity and synergize with conventional therapies. Additionally, we dissect ferroptosis-related gene signatures prognostic of survival and immune microenvironment interactions, revealing their potential for risk stratification and immunotherapy integration.