Context-dependent regulation of ferroptosis sensitivity

Ferroptosis is an important mediator of pathophysiological cell death and an emerging target for cancer therapy. Whether ferroptosis sensitivity is governed by a single regulatory mechanism is unclear. Here, based on the integration of 24 published chemical genetic screens combined with targeted follow-up experimentation, we find that the genetic regulation of ferroptosis sensitivity is highly variable and context-dependent. For example, the lipid metabolic gene acyl-coenzyme A (CoA) synthetase long chain family member 4 (ACSL4) appears far more essential for ferroptosis triggered by direct inhibition of the lipid hydroperoxidase glutathione peroxidase 4 (GPX4) than by cystine deprivation. Despite this, distinct pro-ferroptotic stimuli converge upon a common lethal effector mechanism: accumulation of lipid peroxides at the plasma membrane. These results indicate that distinct genetic mechanisms regulate ferroptosis sensitivity, with implications for the initiation and analysis of this process in vivo. [Display omitted] •An integrated genetic network reveals high variability in ferroptosis regulation•ACSL4 is most important for ferroptosis in response to direct GPX4 inhibition•AGPS is not required for ferroptosis in all contexts•Ferroptotic stimuli converge on plasma membrane lipid peroxidation The genetic regulation of ferroptosis remains poorly understood. Magtanong et al. demonstrate that ACSL4, AGPS, and other lipid metabolic genes are context-dependent ferroptosis regulators that are not universally essential for this process. Results suggest that there may not exist a single ferroptosis genetic regulatory mechanism in all cells and conditions.