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.