Ferroptosis is a form of regulated cell death that results in an accumulation of toxic lipid hydroperoxides. It has been implicated in several human disease models, including cancers, organ failure, and neurodegeneration. Identifying novel regulators and biomarkers for ferroptosis can result in identification of disease states where treatment with ferroptotic inducers or inhibitors can result in a positive outcome for a patient. A CRISPR-dCas9 mediated whole genome activation screen found Gch1 overexpression to have a potent anti-ferroptotic effect. Gch1 overexpression resulted in an increase to the basal levels of endogenous antioxidants including BH4 and CoQ10, as well as protection of a specific class of phospholipids containing polyunsaturated fatty acyl (PUFA) chains. This multipronged defense resulted in strong suppression of ferroptosis. Additionally, we further investigated the protection of this unusual class of phospholipids with two PUFA tails and how their enrichment would result in a change in sensitivity to ferroptosis. We found that the degrees of unsaturation of the acyl chains, as well as differences in head groups of the phospholipids resulted in significant variances in the ability of the phospholipids to induce a strong ferroptotic response. The study of their uptake, subcellular localization, and remodeling pathways can further elucidate biological pathways of ferroptosis.
