Sensitivity of renal cell carcinoma to cuproptosis and cuproptosis related genes FDX1 combined with DLAT as an immunological and prognostic biomarker

Abstract Background Targeting cuproptosis is being considered as a novel and promising therapeutic strategy for the prevention of tumors. Nonetheless, the potential role of cuproptosis and its related genes in renal cell carcinoma (RCC) remains elusive. Methods Cuproptosis differential genes (CDGs) in clear cell renal cell carcinoma (ccRCC) were extracted by GSE53757 dataset and cuproptosis-related genes. The role of CDGs was comprehensively analyzed by multiple public databases. CDGs expression in clinical samples was verified by western blot assay. Cuproptosis inducer elesclomol was utilized to explore the sensitivity of ccRCC to cuproptosis. Drug targets of CDGs were predicted and validated through DrugBank database and molecular docking, respectively. Results The results found that FDX and DLAT exhibited significantly low expression in ccRCC tissues, which was validated in clinical samples. FDX1 and DLAT acted as independent prognostic factors for poor survival in ccRCC patients and showed a strong positive correlation. Functional analysis of differentially expressed genes that were positively or negatively correlated with both FDX1 and DLAT in ccRCC demonstrated that acetyl-CoA biosynthetic process and acetyl-CoA metabolic process were remarkably affected. The methylation levels and sites of FDX1 and DLAT genes were dramatically correlated with overall survival (OS) in ccRCC patients. FDX1 and DLAT expression was strongly correlated with immune infiltration and immune checkpoints. Importantly, elesclomol significantly induced cell death in 786-O and A498 cells, and the expression of FDX1 and DLAT proteins was also markedly up-regulated. Docking results indicate that mitotane, adicicol and dihydrolipoic acid fit reasonably well in the FDX1 and DLAT ligand binding pockets, which may be potential drug targets for FDX1 and DLAT genes. Conclusion The present study implies for the first time the sensitivity of ccRCC to cuproptosis and the combination of targeted FDX1 and DLAT may be a novel therapeutic strategy to induce cuproptosis in ccRCC.