Ferroptosis, a recently identified form of regulated cell death characterized by the irondependent accumulation of lethal lipid peroxidation, has gained increasing attention in cancer
therapy. Ferropt Show more
Ferroptosis, a recently identified form of regulated cell death characterized by the irondependent accumulation of lethal lipid peroxidation, has gained increasing attention in cancer
therapy. Ferroptosis suppressor protein 1 (FSP1), an NAD(P)H-ubiquinone oxidoreductase that
reduces ubiquinone to ubiquinol, has emerged as a critical player in the regulation of ferroptosis.
FSP1 operates independently of the canonical system xc– /glutathione peroxidase 4 pathway, making
it a promising target for inducing ferroptosis in cancer cells and overcoming ferroptosis resistance.
This review provides a comprehensive overview of FSP1 and ferroptosis, emphasizing the importance
of FSP1 modulation and its potential as a therapeutic target in cancer treatment. We also discuss
recent progress in developing FSP1 inhibitors and their implications for cancer therapy. Despite the
challenges associated with targeting FSP1, advances in this field may provide a strong foundation for
developing innovative and effective treatments for cancer and other diseases. Show less
2022 · Proceedings of the National Academy of Sciences · National Academy of Sciences · added 2026-04-21
Mechanisms of defense against ferroptosis (an iron-dependent form of cell death induced by lipid peroxidation) in cellular organelles remain poorly understood, hindering our ability to target ferropto Show more
Mechanisms of defense against ferroptosis (an iron-dependent form of cell death induced by lipid peroxidation) in cellular organelles remain poorly understood, hindering our ability to target ferroptosis in disease treatment. In this study, metabolomic analyses revealed that treatment of cancer cells with glutathione peroxidase 4 (GPX4) inhibitors results in intracellular glycerol-3-phosphate (G3P) depletion. We further showed that supplementation of cancer cells with G3P attenuates ferroptosis induced by GPX4 inhibitors in a G3P dehydrogenase 2 (GPD2)-dependent manner; GPD2 deletion sensitizes cancer cells to GPX4 inhibition-induced mitochondrial lipid peroxidation and ferroptosis, and combined deletion of GPX4 and GPD2 synergistically suppresses tumor growth by inducing ferroptosis in vivo. Mechanistically, inner mitochondrial membrane-localized GPD2 couples G3P oxidation with ubiquinone reduction to ubiquinol, which acts as a radical-trapping antioxidant to suppress ferroptosis in mitochondria. Taken together, these results reveal that GPD2 participates in ferroptosis defense in mitochondria by generating ubiquinol. Show less