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.
Authors
- Florian Rouaud
- Sabrina Ferré (ORCID: https://orcid.org/0000-0002-1379-3025)
- Mirosław Cygler (ORCID: https://orcid.org/0000-0003-4579-1881)
- Michal T. Boniecki (ORCID: https://orcid.org/0000-0002-0854-0891)
- Takashi Tsukamoto (ORCID: https://orcid.org/0000-0002-0216-7520)
- Joséphine Zangari (ORCID: https://orcid.org/0000-0002-8017-2659)
- Evangelia Vartholomaiou (ORCID: https://orcid.org/0000-0002-8664-9999)
- Jean‐Claude Martinou (ORCID: https://orcid.org/0000-0002-9847-2051)
- Kinsey Maundrell
- Sylvie Montessuit
- Roland Lill (ORCID: https://orcid.org/0000-0002-8345-6518)
- Kaushik Bhattacharya (ORCID: https://orcid.org/0000-0001-7147-6776)
- Csaba Szabó (ORCID: https://orcid.org/0000-0003-3110-4235)
- Karim Zuhra (ORCID: https://orcid.org/0000-0003-0186-1817)
- Serge Rudaz (ORCID: https://orcid.org/0000-0002-4180-5417)
- Vinzent Schulz
- Oliver Stehling (ORCID: https://orcid.org/0000-0002-4737-0768)
- Víctor González‐Ruiz (ORCID: https://orcid.org/0000-0001-7204-2363)
- Véronique Serre‐Beinier (ORCID: https://orcid.org/0000-0002-6016-1645)
- Sven‐Andreas Freibert (ORCID: https://orcid.org/0000-0002-8521-2963)
- Michaël Cerezo (ORCID: https://orcid.org/0000-0002-3687-2009)
- Sahra Hanschke
Institutions
- University of Geneva (CH)
- Universidad San Pablo CEU (ES)
- Johns Hopkins University (US)
- University of Fribourg (CH)
- Inserm (FR)
- HES-SO University of Applied Sciences and Arts Western Switzerland (CH)
- Johns Hopkins Medicine (US)
- Steinbeis Foundation (DE)
- University of Saskatchewan (CA)
- Adc Therapeutics (Switzerland) (CH)
- Centre Méditerranéen de Médecine Moléculaire (FR)
- TransCure BioServices (France) (FR)
- Loewe Center for Synthetic Microbiology (DE)
Publication Details
- Journal
- Nature Metabolism
- Published
- 2025-08-12
- DOI
- https://doi.org/10.1038/s42255-025-01339-1
- Citations
- 6
- Primary Topic
- Folate and B Vitamins Research
- Type
- article
- Field-Weighted Citation Impact
- 10.01
Funders
- Deutsche Forschungsgemeinschaft
- Oncosuisse
- Fondation Ernst et Lucie Schmidheiny