Coenzyme A mitigates cystine-deprivation-induced ferroptosis by suppressing the iron-starvation response

The labile iron pool in the cell is required for ferroptosis, a form of regulated cell death resulting from excessive lipid peroxidation and membrane damage. Glutathione (GSH) is critical for lipid-peroxide scavenging, and cysteine is the rate-limiting amino acid in GSH synthesis. Cysteine metabolism intricately intertwines with iron metabolism, either directly by participating in assembly of the iron-sulfur cluster or indirectly through the pantothenate pathway and coenzyme A (CoA) synthesis. However, the regulation of iron homeostasis in cystine (Cys₂)-deprivation-induced ferroptosis is poorly understood. Here, we show that Cys₂ deprivation promotes ferroptosis, at least in part, by activating the iron-starvation response (ISR), and CoA can mitigate ferroptosis by suppressing the ISR. Mechanistically, Cys₂ deprivation promotes the oxidation of cytosolic iron-sulfur clusters to activate the ISR; CoA and related small-molecule thiols in the pantothenate pathway suppress the ISR and ferroptosis by preventing the oxidation of iron-sulfur clusters in Cys₂-deprived cells. Our findings provide important insight into the regulation of the ISR in Cys₂-deprivation-induced ferroptosis, and show that CoA can protect cells from Cys₂-deprivation-induced ferroptosis by suppressing the ISR.