d-cysteine impairs tumour growth by inhibiting cysteine desulfurase NFS1

Abstract 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.