Leukemia stem cells defend ferroptosis by controlling cystine uptake via PIEZO1-HIF1A-SLC7A11 axis

Metabolism reprogramming is intimately accompanied with mitochondrial oxidative stress in driving many human diseases including cancers. Excessive oxidative stress frequently induces cell death including ferroptosis, which needs to be tightly balanced for maintaining cellular homeostasis. However, the precise mechanisms for balancing metabolic reprogramming and oxidative stress under different contexts remain elusive. Here, by studying acute myeloid leukemia stem cells (LSCs) that are largely fueled by OXPHOS, we reveal a defense system of LSCs against oxidative stress-induced ferroptosis. We find that the mechano-sensor PIEZO1 plays key role in promoting acute myeloid leukemia development and maintaining LSCs stemness. 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, our findings reveal that LSCs control cystine uptake through PIEZO1-HIF1A-SLC7A11 axis to defend ferroptosis, representing a unique vulnerability of LSCs.