biostudies-literatureLin CCNIAID NIH HHSNINDS NIH HHSNIGMS NIH HHSe190215https://www.ebi.ac.uk/biostudies/studies/S-EPMC12483566biostudies-literatureUnknown135(19)The cystine-xCT transporter/glutathione/GPX4 axis is the canonical pathway protecting cells from ferroptosis. Whereas GPX4-targeting ferroptosis-inducing compounds (FINs) act independently of mitochondria, xCT-targeting FINs require mitochondrial lipid peroxidation, though the mechanism remains unclear. Because cysteine is also a precursor for coenzyme A (CoA) biosynthesis, here, we demonstrated that CoA supplementation selectively prevented ferroptosis triggered by xCT inhibition by regulating the mitochondrial thioredoxin system. Our data showed that CoA regulated the in vitro enzymatic activity of mitochondrial thioredoxin reductase-2 (TXNRD2) by covalently modifying the thiol group of cysteine (CoAlation) on Cys-483. Replacing Cys-483 with alanine on TXNRD2 abolished its enzymatic actiThe Journal of clinical investigationCoenzyme A protects against ferroptosis via CoAlation of mitochondrial thioredoxin reductase.PMC12483566R01 GM124062R01 NS111588R21 AI149205Lin YTSetayeshpour YChen SYGuruprasad LHayflick SJLin CCZhang GFNguyen TJeong SYMestre AAGout IBanerjee ALin CYChi JTChen YFilonenko VSoderblom EJDunn DEFloyd SRfalseCoenzyme A protects against ferroptosis via CoAlation of mitochondrial thioredoxin reductase.The cystine-xCT transporter/glutathione/GPX4 axis is the canonical pathway protecting cells from ferroptosis. Whereas GPX4-targeting ferroptosis-inducing compounds (FINs) act independently of mitochondria, xCT-targeting FINs require mitochondrial lipid peroxidation, though the mechanism remains unclear. Because cysteine is also a precursor for coenzyme A (CoA) biosynthesis, here, we demonstrated that CoA supplementation selectively prevented ferroptosis triggered by xCT inhibition by regulating the mitochondrial thioredoxin system. Our data showed that CoA regulated the in vitro enzymatic activity of mitochondrial thioredoxin reductase-2 (TXNRD2) by covalently modifying the thiol group of cysteine (CoAlation) on Cys-483. Replacing Cys-483 with alanine on TXNRD2 abolished its enzymatic acti2025-01-01T00:00:00Z2025 Oct2026-06-04T01:53:41.717Z2026-05-04T03:14:04.904ZS-EPMC124835664069442410.1172/JCI190215