Sensitivity of renal cell carcinoma to cuproptosis: a bioinformatics analysis and experimental verification

Purpose: Targeting cuproptosis is considered as a promising therapeutic strategy for the prevention of tumors. However, the potential role of cuproptosis and its related genes in clear cell renal cell carcinoma (ccRCC) remains elusive. The present study aims to explore the sensitivity of ccRCC to cuproptosis and its underlying mechanism. Methods: Cuproptosis differential genes (CDGs) were extracted using the GSE53757 and GSE66272 datasets. A comprehensive analysis of the role of CDGs was conducted through multiple public databases and experiments. Results: It was found that cuproptosis inducer elesclomol significantly induced cell death in 786-O and A498 cells. FDX and DLAT exhibited significantly low expression, which were independent prognostic factors for poor survival, and had a strong positive correlation in ccRCC patients. Functional analysis of differentially expressed genes positively or negatively correlated with both FDX1 and DLAT indicated that acetyl-CoA biosynthetic process and acetyl-CoA metabolic process were remarkably affected. In ccRCC patients, the methylation levels and sites of FDX1 and DLAT genes were dramatically correlated with overall survival (OS). The expressions of FDX1 and DLAT were closely related to immune infiltration and immune checkpoints. Docking results indicated that mitotane, adicicol and dihydrolipoic acid might be potential drug targets for FDX1 and DLAT. Conclusions: Overall, the present study demonstrates the sensitivity of ccRCC to cuproptosis, and targeting the combination of FDX1 and DLAT may be a novel therapeutic strategy to induce cuproptosis in ccRCC.