GSK-3β manipulates ferroptosis sensitivity by dominating iron homeostasis

Ferroptosis is a newly characterized form of non-apoptotic-programmed cell death, which is driven by the lethal accumulation of iron-catalyzed lipid peroxides. Uncontrolled ferroptosis is implicated in the pathogenesis of a group of human diseases, while targeted induction of ferroptosis provides a potent therapeutic design for cancers. During the past decade, the fundamental regulatory circuits of ferroptosis have been identified. In this study, we show that the multifaceted Ser/Thr protein kinase GSK-3 beta acts as a positive modulator of the ferroptosis program. Pharmacological inhibition of GSK-3 beta by selective inhibitor LY2090314 or genetic KD of GSK-3 beta by shRNA potently promotes ferroptotic resistance. GSK-3 beta KD antagonizes the expression of iron metabolic components including DMT1, FTH1, and FTL, leading to the disruption of iron homeostasis and decline in intracellular labile free iron level. Taken together, our findings elaborate an indispensable role of GSK-3 beta in determining ferroptotic sensitivity by dominating cellular iron metabolism, which provides further insight into GSK-3 beta as a target for cancer chemotherapy.

Automated summary

Ferroptosis is a newly characterized form of non-apoptotic-programmed cell death that has implications in human diseases and potential therapeutic applications for cancer. GSK-3 beta acts as a positive modulator of ferroptosis by influencing cellular iron metabolism, indicating its potential as a target for cancer chemotherapy.