Silencing GPx1 Synergizes with Ionizing Radiation to Enhance the Elimination of Leukemia Stem Cells.

Leukemia stem cells (LSCs) are a key factor leading to the recurrence and drug resistance in acute myeloid leukemia (AML). Notably, the persistence of radiotherapy-resistant LSCs has been identified as a critical determinant of post-hematopoietic stem cell transplantation (HSCT) relapse. Herein, we report glutathione peroxidase 1 (GPX1) as a promising target for eliminating LSCs after exposure to ionizing radiation. Silencing GPX1 in LSCs robustly triggers cell death and cell cycle arrest, thereby enhancing the radiosensitivity of LSCs. Specifically, GPX1 maintains the survival and proliferation of LSCs by regulating redox homeostasis. Upon GPX1 knockdown, intracellular reactive oxygen species (ROS) accumulate, which in turn impairs the function of BCL2 and ultimately triggers LSC apoptosis. After radiation exposure, ROS scavengers can effectively rescue GPX1 knockdown-induced LSC apoptosis and restore their impaired proliferative capacity. Accordingly, our study reveals GPX1 function in LSC maintenance and radiation tolerance, providing a therapeutic opportunity for ablating LSCs and for AML targeted therapy.