The signature genes of cuproptosis associates with tumor immune microenvironment and predicts prognosis in kidney renal clear cell carcinoma.

Background: Cuproptosis is a new form of cell death, which has great potential to be developed in tumors treatment. Our study aimed to explore the predictive value of cuproptosis-related genes (CRGs) in various cancers, with a focus on kidney renal clear cell carcinoma (KIRC).

Method: A total of 9502 pan-cancer patients from TCGA cohort were enrolled. The relationships between CRGs and overall survival (OS) or disease-free survival (DFS) were analyzed. Gene Set Variation Analysis (GSVA) enrichment analysis was performed to explore the expression differences of CRGs. Multivariate Cox regression analysis was used to evaluate the association between GSVA scores and patient survival. KEGG and GO analyses were employed to identify the biological functions and pathways. The expression and prognostic characteristics of FDX1 were examined to evaluate the correlation between FDX1 and KIRC. Cell experiments were conducted to verify whether FDX1 was involved in cuproptosis of Caki-1 cells induced by Elesclomol.

Results: Positive cuproptosis signature genes(pos.cu.sig) exhibited the correlation with prognosis in KIRC, and all of these genes showed differential expression between KIRC and normal tissues. The GSVA score of pos.cu.sig was associated with excellent survival (HR=0.61, <0.05), which can also serve as an independent prognostic factor for KIRC. There was a close correlation between pos.cu.sig and the tumor immune microenvironment in KIRC by KEGG and GO analysis. FDX1 expression was correlated with KIRC grade and positively associated with prognosis in KIRC patients. Compared with the control group, cell proliferation and migration were significantly inhibited, FDX1 expression was up-regulated, and Fe-S cluster protein content was decreased of Caki-1 cells after Elesclomol treatment.

Conclusions: This study provides compelling evidence that cuproptosis is closely linked to the prognosis of KIRC. FDX1 holds promise as a viable biomarker and therapeutic target for assessing the effectiveness of tumor immunotherapy in KIRC.