| Summary: | Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cancer. Cuproptosis is suggested to be a novel therapy target for cancer treatment. However, the function of cuproptosis and its key regulator <i>FDX1</i> in ccRCC remains unclear. In this study, we adequately explored the prognostic factors, clinicopathological characteristics, and function of <i>FDX1</i> in ccRCC. We found that the expression of <i>FDX1</i> was significantly downregulated in ccRCC samples. Patients with a higher <i>FDX1</i> expression had a significantly better prognosis, including overall survival (OS) (Hazard ratio (HR): 2.54, 95% confidence interval (CI): 1.82–3.53, <i>p</i> < 0.001), disease-specific survival (DSS) (HR: 3.04, 95% CI: 2.04–4.54, <i>p</i> < 0.001), and progression-free survival (PFS) (HR: 2.54, 95% CI: 1.82–3.53, <i>p</i> < 0.001). <i>FDX1</i> was a clinical predictor to stratify patients into the high or low risk of poor survival, independent of conventional clinical features, with the area under the ROC curve (AUC) of 0.658, 0.677, and 0.656 for predicting the 5-year OS, DSS, and PFS. The nomogram model based on <i>FDX1</i> had greater predictive power than other individual prognostic parameters. <i>FDX1</i> mainly participated in the oxidative-related process and mitochondrial respiration-related processes but was not associated with immune infiltration levels. In conclusion, the cuproptosis key regulator <i>FDX1</i> could serve as a potential novel prognostic biomarker for ccRCC patients.
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