Targeting Ferroptosis Pathways to Enhance Therapeutic Outcomes in Acute Myeloid Leukemia: A Systematic Review

Background: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy in which relapse and treatment resistance remain major clinical challenges. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a potential therapeutic vulnerability in AML. Objectives: This study aimed to systematically evaluate ferroptosis-related mechanisms, therapeutic targeting strategies, and their translational relevance in AML. Methods: This systematic review followed PRISMA 2020 and was prospectively registered in PROSPERO. Eligible studies were primary experimental or translational investigations using human AML cell lines and/or adult patient-derived or ex vivo AML material. In vitro components were appraised descriptively using QUIN domains, whereas patient-derived evidence was assessed using structured methodological domains. Ferroptosis-specific confirmation and translational relevance were evaluated separately. Results: Eighteen studies met the eligibility criteria. Recurrent mechanisms involved the SLC7A11/GSH/GPX4 axis, NRF2-mediated redox adaptation, iron handling and ferritinophagy, lipid remodeling, ceramide metabolism, and nanoparticle-mediated redox disruption. Eight studies met the review-defined criteria for confirmed ferroptosis, seven were strongly supportive, and three were suggestive or ferroptosis-associated. Several approaches reduced AML cell viability or enhanced sensitivity to established therapies. No clinical intervention studies were identified. Conclusions: Ferroptosis-related pathways represent biologically relevant and potentially exploitable preclinical vulnerabilities in AML. However, evidence remains heterogeneous and predominantly preclinical, warranting standardized ferroptosis-specific validation and larger patient-derived studies before clinical translation.