FDX1 expression predicts favourable prognosis in clear cell renal cell carcinoma identified by bioinformatics and tissue microarray analysis

Abstract

Ferredoxin 1 (FDX1), an iron-sulphur protein, is responsible for electron transfer in a range of metabolic redox reactions. Clear cell renal cell carcinoma (ccRCC) is an aggressive cancer characterised by metabolic reprogramming, and FDX1 is a critical regulator of cuproptosis. However, the expression profile and prognostic value of FDX1 associated with clinicopathological features in ccRCC remain largely unelucidated. In this study, we integrated a series of public bioinformatic analysis to explore the mRNA and protein profiles of FDX1 across human cancers and cell lines and validated its expression and prognostic value, especially in ccRCC. In this study, FDX1 mRNA and protein expression were aberrantly downregulated and associated with ccRCC grade, stage, and nodal metastasis, whereas in adjacent non-tumour kidney tissue, it was abundantly expressed and cytoplasmically localised in renal tubular epithelial cells. Multivariate analysis indicated that low FDX1 expression contributed to unfavourable overall and disease-free survival. The functional enrichment of FDX1 co-expressed genes in ccRCC involved mainly mitochondrial dysfunction in various metabolic processes and biological oxidation, besides iron-sulphur cluster biogenesis. Furthermore, FDX1 modulates immunological infiltration to affect prognosis. Thus, FDX1 downregulation is mechanistically because of ccRCC tumourigenesis and is a promising prognostic biomarker to stratify patients with ccRCC.

Confirmation of the predictive function of cuproptosis-related gene FDX1 in clear cell renal carcinoma using qRT-PCR and western blotting

“…Our research also showed that FDX1 methylation could be observed during transcription, and the transcribed protein was expressed in normal tissues but not in tumors. This finding is supported by those of other studies [ 12 , 19 , 20 ]. Moreover, high FDX1 expression was associated with better OS according to TCGA and Array Express databases ( P < 0.05).…”

“…In our study, we used an external database and qRT-PCR experiments for validation. The experimental results obtained by Zhang and Huang are consistent with our results [ 12 , 19 ]. Our research also showed that FDX1 methylation could be observed during transcription, and the transcribed protein was expressed in normal tissues but not in tumors.…”

“…Multiple studies referencing TCGA and GEO databases have suggested decreased FDX1 expression in ccRCC tissues compared to that in normal tissues [ 12 , 19 ]. In our study, we used an external database and qRT-PCR experiments for validation.…”

Frontier knowledge and future directions of programmed cell death in clear cell renal cell carcinoma

“…The Cuproposis score was strongly correlated with the infiltration levels of various immune cells in the TME [ 113 , 114 ]. As a critical regulator of cuproptosis, FDX1 sparked greater interest in favorable prognosis in ccRCC than other individual prognostic parameters [ 115 , 116 ]. Similarly, cuproptosis-related lncRNA also show pretty predicting potential [ 117 ].…”

The role of novel programmed cell death in head and neck squamous cell carcinoma: from mechanisms to potential therapies

“…Because DLAT and DLST are components of the TCA cycle, FDX1 then directs oligomerization of DLAT and DLST, reducing their levels; this implies that cuproptosis targets components of the TCA cycle ( Tsvetkov et al, 2022 ). It has been demonstrated that mitochondrial respiration is associated with copper death; excess copper promotes aggregation of lipoylated protein and reduces iron-sulfur cluster protein; this triggers aggregation and dysregulation of these proteins, blocking the TCA cycle, leading to proteotoxic stress and ultimately cell death ( Huang et al, 2022 ). Briefly, cuproptosis mainly depends on intracellular copper accumulation and the TCA cycle, while FDX1 and proteolipidation are key regulators ( Figure 4 ).…”