Regulating Ferroptosis in Leukemic Stem Cells: From Stemness Preservation to Targeted Differentiation Strategies

The persistence and drug resistance of leukemic stem cells (LSCs) are major challenges in the treatment of acute myeloid leukemia (AML). Ferroptosis, a novel form of programmed cell death, has emerged as a promising strategy for eradicating LSCs. This review provides a systematic analysis of LSC ferroptosis resistance and explores the interplay between iron metabolism, lipid peroxidation, and antioxidant defense mechanisms. We propose a novel predictive model based on single-cell multiomics data that integrates iron homeostasis regulators (TfR1, GPX4, and FTH1) to assess the susceptibility of LSCs to ferroptosis. A key innovation of this study was the in-depth exploration of LSC ferroptotic heterogeneity and its interaction with the tumor microenvironment, shedding light on new approaches for precision AML therapy. Based on these findings, we introduced an innovative treatment paradigm combining ferroptosis inducers (e.g., erastin, RSL3) with immunotherapies (such as PD-L1 inhibitors and CAR-T cell therapy) to enhance LSC clearance and minimize measurable residual disease (MRD). This review fills a critical knowledge gap in the study of ferroptosis in LSCs, providing a theoretical foundation and translational insights for future AML treatment strategies.