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

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.