Nature https://doi.org/10.1038/s41586-019-1707-0 (2019)
Nature https://doi.org/10.1038/s41586-019-1705-2 (2019)
Ferroptosis is a form of iron-dependent cell death caused by elevated lipid peroxidation. Glutathione peroxidase 4 (GPX4)-mediated conversion of phospholipid hydroperoxides into non-toxic lipid alcohols is thought to mitigate ferroptosis, and GPX4 inhibitors promote ferroptosis in certain cancer cells. To explore alternative mechanisms to prevent ferroptosis, Besuker et al. performed a synthetic lethal CRISPR–Cas screen in a ferroptosis-resistant cell line, and Doll et al. screened for genes that could complement GPX4 inhibition. In both cases, they revealed that an NADH-dependent coenzyme Q oxidoreductase, ferroptosis-suppressor protein 1 (FSP1), protected cells against ferroptosis. FSP1 required N-myristoylation and plasma-membrane association for its antiferroptotic activity, and it reduced coenzyme Q10 in the lipid bilayer to (re)generate radical-trapping antioxidants that inhibit lipid peroxidation. The increased expression of FSP1 was correlated with ferroptosis resistance in numerous cancer cell lines, and inhibition of FSP1 resulted in increased sensitivity to ferroptosis inducers. Altogether, these findings reveal a parallel pathway that mitigates ferroptosis together with GPX4.