The potential of targeting cuproptosis in the treatment of kidney renal clear cell carcinoma

Renal cancer: signaling pathways and advances in targeted therapies

“…As a cofactor of various enzymes, copper participates in regulating multiple physiological processes within cells, such as the function of cytochrome coxidase ( COX ), which requires the involvement of copper ions to complete cellular respiration. 115 However, recent research indicates that excessive intracellular copper concentrations can trigger a unique form of cell death known as “cuproptosis.” 116 The primary mechanism of cuproptosis involves the binding of excess copper to succinylated proteins in the tricarboxylic acid cycle, leading to abnormal aggregation of lipidation‐related proteins and degradation of iron–sulfur cluster proteins, ultimately resulting in cell death due to an intracellular protein toxicity stress response. 116 Appropriate levels of copper can induce autophagy‐mediated degradation of GPX4 , thereby promoting ferroptosis, indicating a crosstalk between ferroptosis and cuproptosis.…”

“…Currently, various forms of cell death, such as apoptosis, necrosis, pyroptosis, ferroptosis, and autophagic cell death, have been extensively studied in ccRCC 22 ; however, the role of cuproptosis in the pathogenesis and progression of ccRCC remains largely unexplored. 115 Multiple studies have demonstrated that copper levels are elevated to varying degrees in ccRCC patients, suggesting the potential involvement of cuproptosis in the pathogenesis and progression of ccRCC. For instance, Pirincci et al.…”

“…Cuproptosis may contribute to metabolic reprogramming in ccRCC by modulating the activity of crucial mitochondrial enzymes. 115 Dysregulation of the VHL/HIF pathway and perturbations in copper homeostasis may synergistically contribute to metabolic reprogramming in ccRCC, offering a novel insight into the role of cuproptosis in the initiation and progression of ccRCC. Mitochondrial dysfunction and metabolic reprogramming are hallmark features of ccRCC.…”

“… 121 Deletion of the VHL gene and aberrant activation of the HIF pathway are pivotal in driving the metabolic reprogramming of ccRCC. 115 Deletion of the VHL gene results in enhanced stability of HIF‐1α and HIF‐2α proteins, leading to upregulated glycolysis and consequently diminished mitochondrial respiration and energy metabolism. 115 Subsequent investigations have revealed an intricate regulatory interplay between copper and the HIF‐1 pathway.…”

“… 115 Deletion of the VHL gene results in enhanced stability of HIF‐1α and HIF‐2α proteins, leading to upregulated glycolysis and consequently diminished mitochondrial respiration and energy metabolism. 115 Subsequent investigations have revealed an intricate regulatory interplay between copper and the HIF‐1 pathway. 115 On the one hand, copper can enhance the expression and transcriptional activity of HIF‐1 , thereby promoting the expression of its downstream target genes, such as VEGF .…”