As an essential metal co-factor, Cu accumulation has been linked with tumorigenesis, but the underlying mechanism remains to be fully defined. A study now reports that Cu, as a subunit of cytochrome c oxidase (CuCOX), promotes the development of clear cell renal cell carcinoma (ccRCC) through metabolic reprogramming.

The authors first observed positive correlation between the level of Cu and disease progression in patients with ccRCC and demonstrated that a low-Cu diet suppresses tumour growth in xenograft models. RNA sequencing and metabolomics analysis revealed Cu-mediated metabolism remodelling in renal cancer cells, especially in terms of biosynthetic and electron transport chain activity in mitochondria. The authors further showed that Cu-induced CuCOX activity is indispensable for ccRCC progression by regulating glucose-derived glutathione and maintaining redox homeostasis. Lastly, cohort analysis uncovered upregulated Cu and glutathione metabolism and increased oxidative phosphorylation correlated with ccRCC development.

作为一种必需金属辅助因子，Cu 积累与肿瘤发生有关，但其潜在机制仍有待完全明确。现在的一项研究报道，Cu 作为细胞色素 c 氧化酶 （CuCOX） 的一个亚基，通过代谢重编程促进透明细胞肾细胞癌 （ccRCC） 的发展。

作者首先观察到 ccRCC 患者的 Cu 水平与疾病进展呈正相关，并证明低 Cu 饮食会抑制异种移植模型中的肿瘤生长。RNA 测序和代谢组学分析揭示了肾癌细胞中 Cu 介导的代谢重塑，尤其是在线粒体中的生物合成和电子传递链活性方面。作者进一步表明，Cu 诱导的 CuCOX 活性通过调节葡萄糖衍生的谷胱甘肽和维持氧化还原稳态，对 ccRCC 进展是必不可少的。最后，队列分析发现 Cu 和谷胱甘肽代谢上调，氧化磷酸化增加与 ccRCC 发展相关。