The potential value of cuprotosis (copper-induced cell death) in the therapy of clear cell renal cell carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) accounts for 75% of the total incidence of renal cancer, and every year the number of morbidity and mortality increases, posing a serious threat to public health. The current main treatment methods for kidney cancer include drug-targeted therapy and immunotherapy. Although there are many treatment options for kidney cancer, they all have limitations, including drug resistance, unsatisfied long-term benefits, and adverse effects. Therefore, it is crucial to identify more effective therapeutic targets. As a newly discovered mechanism of cell death, copper-induced cell death (cuprotosis) is closely related to changes in cell metabolism, particularly in copper metabolism. Current studies have shown that the key signaling pathway of cuprotosis, the FDX1 (Ferredoxin 1)-LIAS (Lipoic Acid Synthetase) axis, plays an important role in the regulation of cellular oxidative stress, which can directly affect cell survival via inducing or promoting cancer cell death. Therefore, we speculated that this regulatory cell death mechanism might serve as a potential therapeutic target for the clinical treatment of renal cancer. To test this, we first performed a pan-cancer analysis based on cuprotosis-related genomic and transcriptomic levels to reveal the expression of cuprotosis in cancer. Next, GSVA-clustering analysis was performed with data from the Cancer Genome Atlas (TCGA) cohort, and the cohort was divided into three clusters according to the gene enrichment levels of cuprotosis marker genes. In addition, we analyzed the potential of using cuprotosis in clinical treatment from multiple perspectives, including chemotherapeutic drug susceptibility test, immune target inhibition treatment responsiveness, and histone modification. Combining the results of multi-omics analysis, we focused on the feasibility of this novel regulatory cell death mechanism in ccRCC treatment and further constructed a prognostic model. Finally, we verified our results by integrating the patient's gene expression information and radiomics information. Our study provides new insights into the development and clinical application of targeting cuprotosis pathway.