罗切斯特大学Isaac S. Harris课题组取得一项新突破。他们发现了细胞外谷胱甘肽的分解代谢提供半胱氨酸以支持肿瘤。2026年3月18日出版的《自然》发表了这项成果。

在这里，该课题组人员发现细胞内谷胱甘肽的消耗不会改变肿瘤的生长，而细胞外谷胱甘肽在肿瘤微环境中非常丰富，突出了肿瘤外谷胱甘肽的潜在重要性。在胱氨酸缺乏的情况下，补充谷胱甘肽可以挽救癌细胞的生存和生长，这种挽救依赖于γ-谷氨酰转移酶的分解代谢活性。最后，γ-谷氨酰转移酶活性的药理靶向可防止循环谷胱甘肽的分解，降低肿瘤的半胱氨酸水平并减缓肿瘤的生长。他们的发现表明谷胱甘肽作为氨基酸储存库在支持肿瘤方面的非规范作用。对于癌症患者来说，剥夺肿瘤细胞外谷胱甘肽或抑制其分解是一种潜在的治疗方法。

此外，这些发现改变了他们对谷胱甘肽以及包括半胱氨酸在内的氨基酸如何供应给细胞的看法。

据了解，限制肿瘤中的氨基酸是一种新兴的治疗策略，具有很大的前景。谷胱甘肽（GSH）作为半胱氨酸、谷氨酸和甘氨酸的三肽，虽然通常被认为是具有促肿瘤能力的细胞内抗氧化剂，但它可以被分解代谢释放氨基酸。谷胱甘肽衍生的氨基酸在多大程度上对癌症至关重要尚不清楚。

附：英文原文

Title: Catabolism of extracellular glutathione supplies cysteine to support tumours

Author: Hecht, Fabio, Zocchi, Marco, Tuttle, Emily T., Ward, Nathan P., Alimohammadi, Fatemeh, Khan, Amal Afzal, Gomes, Veronica C., Smith, Bradley, Twardowski, Jennifer J., Mills, Bradley N., Welle, Kevin A., Ghaemmaghami, Sina, Zhou, Zhuoran, Gan, Yuhan, Kang, Yun Pyo, Cazarin, Juliana, Soares, Zamira G., Ozgurses, Mete Emir, Zhao, Huiping, Sheehan, Colin, Cognet, Guillaume, Munger, Lila D., Trivedi, Dhvani, Asantewaa, Gloria, Blick-Nitko, Sara K., Zoeller, Jason J., Chen, Ying, Vasiliou, Vasilis, Turner, Bradley M., Mello, Stephano S., Altman, Brian J., Muir, Alexander, Coloff, Jonathan L., Munger, Joshua, DeNicola, Gina M., Harris, Isaac S.

Issue&Volume: 2026-03-18

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.

DOI: 10.1038/s41586-026-10268-2

Source: https://www.nature.com/articles/s41586-026-10268-2