Qian Xue, Ziyuan Chen, Jiao Yang, Kaixuan Ren, Xiaofen Li, Xi Chen, Ding Yan, Yuan Wang, Yuan Wang, Jinbao Liu, Xin Chen
Together, these findings reveal copper deprivation as a robust condition driving ferroptosis resistance and suggest that dietary or pharmacological copper modulation could provide new strategies to fine-tune ferroptosis in cancer and tissue injury.
Copper is an essential trace element that governs diverse cellular functions and influences cell fate. However, how cells adapt to copper deprivation remains poorly understood. Here, we identify a copper-ferroptosis regulatory axis mediated by the cystine transporter SLC7A11. We show that copper loss, induced either by silencing of the copper importer SLC31A1 or by pharmacological chelation, leads to a marked upregulation of SLC7A11. This adaptive response enhances glutathione synthesis, bolsters antioxidant defenses, and protects cells from ferroptosis. Mechanistically, copper deprivation activates AMPK, which stabilizes the transcription factor NRF2 to drive SLC7A11 expression. Functionally, SLC31A1 depletion diminishes ferroptosis-dependent tumor suppression in xenograft models, while dietary copper restriction alleviates ferroptosis-mediated pancreatic injury in experimental acute pancreatitis. Together, these findings reveal copper deprivation as a robust condition driving ferroptosis resistance and suggest that dietary or pharmacological copper modulation could provide new strategies to fine-tune ferroptosis in cancer and tissue injury.