PIEZO1 is Required for Acute Myeloid Leukemia Progression and Leukemia Stem Cell Maintenance via HIF1A‐SLC7A11 Axis‐Mediated Ferroptosis Defense

Acute myeloid leukemia (AML) is a highly aggressive hematologic malignancy that arises from leukemia stem cells (LSCs) transformed from normal hematopoietic stem progenitor cells (HSPCs). Compared to normal HSPCs, LSCs acquire various adaptive properties that enable their survival and regenerative capacity under environmental challenges. However, the key regulators underlying these adaptative features in AML LSCs remain largely unknown. Here, the mechanosensor PIEZO1 as a key factor in promoting acute myeloid leukemia progression and maintaining LSC stemness by HIF1A-SLC7A11 axis-mediated ferroptosis defense is uncovered. PIEZO1 deletion impairs cystine uptake and induces ROS and lipid peroxidation, causing ferroptosis of leukemia cells. Mechanistically, HIF1A mediates the function of PIEZO1 by transcriptionally regulating the expression of SLC7A11 and SLC3A2. Further, inhibition of PIEZO1 and SLC7A11 suppresses LSC function and contributes to AML treatment. In summary, this findings reveal that LSCs control cystine uptake through the PIEZO1-HIF1A-SLC7A11 axis to defend against ferroptosis, representing a unique vulnerability of LSCs.