d-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 respiration, nucleotide metabolism and maintenance of genome integrity, leading to decreased oxygen consumption, DNA damage and cell cycle arrest. d-Cys administration diminishes tumour growth of human triple-negative breast cancer cells implanted orthotopically into the mouse mammary gland. Hence, d-Cys could represent a simple therapy to selectively target those forms of cancer characterized by overexpression of xCT/CD98. Zangari et al. show that d-cysteine targets NFS1, thus affecting Fe–S cluster biogenesis and impairing tumour growth.