biostudies-literatureZangari JOncosuisseSwiss National Science FoundationDeutsche ForschungsgemeinschaftDeutsche Forschungsgemeinschaft (German Research Foundation)Fondation Ernst et Lucie SchmidheinyOncosuisse (OCS)1646-1662https://www.ebi.ac.uk/biostudies/studies/S-EPMC12373508biostudies-literatureUnknown7(8)Selective targeting of cancer cells is a major challenge for cancer therapy. Many cancer cells overexpress the cystine/glutamate antiporter xCT/CD98, an L-cystine transport system that strengthens antioxidant defences, thereby promoting tumour survival and progression. Here, we show that the D-enantiomer of cysteine (D-Cys) is selectively imported into xCT/CD98-overexpressing cancer cell lines and impairs their proliferation, particularly under high oxygen concentrations. Intracellular D-Cys specifically inhibits the mitochondrial cysteine desulfurase NFS1, a key enzyme of cellular iron-sulfur protein biogenesis, by blocking sulfur mobilization due to steric constraints. NFS1 inhibition by D-Cys affects all cellular iron-sulfur cluster-dependent functions, including mitochondrial respiratiNature metabolismD-cysteine impairs tumour growth by inhibiting cysteine desulfurase NFS1.PMC12373508KFS-4434-02-2018Koselleck grant LI 415/6 and SPP 1927; LI 415/7179421Zuhra KTsukamoto TCerezo MLill RSchulz VFreibert SABoniecki MTMaundrell KVartholomaiou EMartinou JCHanschke SFerre SMCygler MSzabo CRouaud FGonzalez-Ruiz VRudaz SSerre-Beinier VMontessuit SStehling OZangari JBhattacharya KfalseD-cysteine impairs tumour growth by inhibiting cysteine desulfurase NFS1.Selective targeting of cancer cells is a major challenge for cancer therapy. Many cancer cells overexpress the cystine/glutamate antiporter xCT/CD98, an L-cystine transport system that strengthens antioxidant defences, thereby promoting tumour survival and progression. Here, we show that the D-enantiomer of cysteine (D-Cys) is selectively imported into xCT/CD98-overexpressing cancer cell lines and impairs their proliferation, particularly under high oxygen concentrations. Intracellular D-Cys specifically inhibits the mitochondrial cysteine desulfurase NFS1, a key enzyme of cellular iron-sulfur protein biogenesis, by blocking sulfur mobilization due to steric constraints. NFS1 inhibition by D-Cys affects all cellular iron-sulfur cluster-dependent functions, including mitochondrial respirati2025-01-01T00:00:00Z2025 Aug2026-05-08T06:48:47.386Z2026-04-07T23:31:07.794ZS-EPMC123735084079710110.1038/s42255-025-01339-1