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Interestingly, several studies showed that cytokines and stress stimuli such as TNF-, interleukins, FAS ligand, heat shock, UV irradiation and also stressors that deplete glutathione such as ROS and 4HNE can activate sphingomyelinase, which leads to increased ceramide production 58,59,60

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In addition, holistic GPX4 deletion in mice resulted in embryonic death, while conditional knockout of GPX4 in mice exhibited abnormalities in multiple organs, including the brain, kidney, endothelium, and liver (Maiorino et al., 2018)