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.