Abstract
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-3β acts as a positive modulator of the ferroptosis program. Pharmacological inhibition of GSK-3β by selective inhibitor LY2090314 or genetic KD of GSK-3β by shRNA potently promotes ferroptotic resistance. GSK-3β 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-3β in determining ferroptotic sensitivity by dominating cellular iron metabolism, which provides further insight into GSK-3β as a target for cancer chemotherapy.
Highlights
Ferroptosis is a newly characterized form of regulated cell death [1]
Lipid peroxidation occurring in polyunsaturated fatty acids (PUFAs)-containing phospholipids is largely dependent on enzymatic reactions, the exact mechanisms are less understood
Inhibition of GSK-3β kinase activity significantly promotes and lipid reactive oxygen species (ROS) accumulation, which further strengthen the conclusion that GSK-3β can promote cell ferroptosis
Summary
Ferroptosis is a newly characterized form of regulated cell death [1] This iron-dependent cell death is sharply distinct from the previously defined programmed cell death including apoptosis, necroptosis, and pyroptosis, at morphological, genetic, and biochemical levels. Ferroptosis suppressor protein 1 (FSP1) [3, 4] and dihydroorotate dehydrogenase (DHODH) [5] operate in parallel to GPX4 to antagonize lipid peroxidation and restrain ferroptosis. Lipid peroxidation occurring in polyunsaturated fatty acids (PUFAs)-containing phospholipids is largely dependent on enzymatic reactions, the exact mechanisms are less understood. Acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) catalyze the PUFAs esterification for the subsequent incorporation into membrane phospholipids, shape the cellular lipid composition and define the ferroptotic sensitivity [9, 10]. It has been recently reported that POR (cytochrome P450 oxidoreductase) and CYB5R1 (NADH-cytochrome b5 reductase 1) promote lipid peroxidation and facilitate ferroptosis [11, 12]
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