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<p>Selective targeting of cancer cells is a major challenge for cancer therapy. Many cancer cells overexpress the cystine/glutamate antiporter xCT/CD98, an <span>l</span>-cystine transport system that strengthens antioxidant defences, thereby promoting tumour survival and progression. Here, we show that the <span>d</span>-enantiomer of cysteine (<span>d</span>-Cys) is selectively imported into xCT/CD98-overexpressing cancer cell lines and impairs their proliferation, particularly under high oxygen concentrations. Intracellular <span>d</span>-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 <span>d</span>-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. <span>d</span>-Cys administration diminishes tumour growth of human triple-negative breast cancer cells implanted orthotopically into the mouse mammary gland. Hence, <span>d</span>-Cys could represent a simple therapy to selectively target those forms of cancer characterized by overexpression of xCT/CD98.</p>

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d-cysteine impairs tumour growth by inhibiting cysteine desulfurase NFS1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月12日

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  • Joséphine Zangari,
  • Oliver Stehling,
  • Sven A. Freibert,
  • Kaushik Bhattacharya,
  • Florian Rouaud,
  • Veronique Serre-Beinier,
  • Kinsey Maundrell,
  • Sylvie Montessuit,
  • Sabrina Myriam Ferre,
  • Evangelia Vartholomaiou,
  • Vinzent Schulz,
  • Karim Zuhra,
  • Víctor González-Ruiz,
  • Sahra Hanschke,
  • Takashi Tsukamoto,
  • Michaël Cerezo,
  • Csaba Szabo,
  • Serge Rudaz,
  • Michal T. Boniecki,
  • Miroslaw Cygler,
  • Roland Lill,
  • Jean-Claude Martinou

摘要

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.