Protein CoAlation on TXNRD2 regulates mitochondrial thioredoxin system to protect against ferroptosis

Cystine-xCT transporter-Glutathione (GSH)-GPX4 axis is the canonical pathway to protect against ferroptosis. While not required for ferroptosis-inducing compounds (FINs) targeting GPX4, FINs targeting the xCT transporter require mitochondria and its lipid peroxidation to trigger ferroptosis. However, the mechanism leading to the distinct difference between these FINs is still unknown. Given that cysteine is also required for coenzyme A (CoA) biosynthesis, here, we showed that CoA supplementation specifically prevents ferroptosis induced by xCT inhibitors but not GPX4 inhibitors.