2. Academic Validation
  3. Catabolism of extracellular glutathione supplies cysteine to support tumours

Catabolism of extracellular glutathione supplies cysteine to support tumours

  • Nature. 2026 Mar 18. doi: 10.1038/s41586-026-10268-2.
Fabio Hecht # 1 2,  Marco Zocchi # 3 4,  Emily T Tuttle 3 4,  Nathan P Ward 5,  Fatemeh Alimohammadi 3 4,  Amal Afzal Khan 3 6,  Veronica C Gomes 3 4,  Bradley Smith 4,  Jennifer J Twardowski 4,  Bradley N Mills 4 7,  Kevin A Welle 8,  Sina Ghaemmaghami 8 9,  Zhuoran Zhou 3,  Yuhan Gan 3,  Yun Pyo Kang 5,  Juliana Cazarin 3 4,  Zamira G Soares 3 4,  Mete Emir Ozgurses 10,  Huiping Zhao 10,  Colin Sheehan 11,  Guillaume Cognet 11,  Lila D Munger 3 4,  Dhvani Trivedi 3 4,  Gloria Asantewaa 3 4 12,  Sara K Blick-Nitko 3 4,  Jason J Zoeller 13,  Ying Chen 14,  Vasilis Vasiliou 14,  Bradley M Turner 6,  Stephano S Mello 3 4,  Brian J Altman 3 4,  Alexander Muir 11,  Jonathan L Coloff 10,  Joshua Munger 4 12,  Gina M DeNicola 5,  Isaac S Harris 15 16 17
Affiliations

Affiliations

  • 1 Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA. fabio_hechtcastromedeiro@urmc.rochester.edu.
  • 2 Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA. fabio_hechtcastromedeiro@urmc.rochester.edu.
  • 3 Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.
  • 4 Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
  • 5 Department of Metabolism and Physiology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
  • 6 Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA.
  • 7 Department of Surgery, University of Rochester Medical Center, Rochester, NY, USA.
  • 8 University of Rochester Mass Spectrometry Resource Laboratory, Rochester, NY, USA.
  • 9 Department of Biology, University of Rochester, Rochester, NY, USA.
  • 10 Department of Physiology and Biophysics, University of Illinois College of Medicine, University of Illinois Cancer Center, Chicago, IL, USA.
  • 11 Ben May Department of Cancer Research, University of Chicago, Chicago, IL, USA.
  • 12 Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, USA.
  • 13 Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
  • 14 Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA.
  • 15 Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA. isaac_harris@urmc.rochester.edu.
  • 16 Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA. isaac_harris@urmc.rochester.edu.
  • 17 Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, USA. isaac_harris@urmc.rochester.edu.
  • # Contributed equally.
PMID: 41851454 DOI: 10.1038/s41586-026-10268-2
Abstract

Restricting Amino acids from tumours is an emerging therapeutic strategy with substantial promise1. Although typically considered an intracellular antioxidant with tumour-promoting capabilities2, glutathione (GSH), as a tripeptide of cysteine, glutamate and glycine, can be catabolized to release Amino acids. The extent to which GSH-derived Amino acids are essential to cancers is unclear. Here we show that depletion of intracellular GSH does not alter tumour growth and extracellular GSH is highly abundant in the tumour microenvironment, highlighting the potential importance of GSH outside tumours. Supplementation with GSH rescues Cancer cell survival and growth in cystine-deficient conditions, and this rescue depends on the catabolic activity of γ-glutamyltransferases. Finally, pharmacological targeting of the activity of γ-glutamyltransferases prevents the breakdown of circulating GSH, reduces tumour cysteine levels and slows tumour growth. Our findings indicate a non-canonical role for GSH in supporting tumours by acting as a reservoir of Amino acids. Depriving tumours of extracellular GSH or inhibiting its breakdown is potentially a therapeutically tractable approach for patients with Cancer. Furthermore, these findings change our view of GSH and how Amino acids, including cysteine, are supplied to cells.

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