Multi-omics pan-cancer study of cuproptosis core gene and its role in kidney renal clear cell carcinoma.

Background: The mechanism of copper-induced cellular death was newly discovered and termed cuproptosis. Inducing cuproptosis in cancer cells is well anticipated for its curative potential in treating tumor diseases. However, ferredoxin 1 (), the core regulatory gene in cuproptosis, is rarely studied, and the regulation of in tumor biology remains obscure. A comprehensive pan-cancer analysis of is needed.

Methods: Thirty-three types of tumors were included with paired normal tissues in The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) datasets. The interaction between transcription, protein, phosphorylation, and promoter methylation levels was analyzed. Survival, immune infiltration, single-cell expression, -related tumor mutational burden (TMB), microsatellite instability (MSI), stemness, tumor immune dysfunction and exclusion (TIDE), and immunotherapy-related analyses were performed. protein expression was assessed by kidney renal clear cell carcinoma (KIRC) tissue microarray immunohistochemistry. The function of in KIRC was further explored by experiments in 786-O cell lines .

Results: is highly expressed in 15 tumor types and lowly expressed in 11 tumor types. The corresponding changes in protein expression, phosphorylation, and promoter methylation level of have been described in several tumors. Survival analysis showed that was related to favorable or poor overall survival in eight tumors and progression-free survival in nine tumors. Immune infiltration and single-cell analysis indicated the indispensable role of expression in macrophages and monocytes. Multiple established immunotherapy cohorts suggested that may be a potential predictor of treatment effects for tumor patients. Tissue microarray analysis showed decreased expression in KIRC patients' tumor tissues. Knockdown of resulted in the downregulation of cuproptosis in kidney renal clear tumor cells. Mechanistically, the -associated gene expression signature in KIRC is related to the enrichment of genes involved in the tricarboxylic acid (TCA) cycle, NOTCH pathway, etc. Several NOTCH pathway genes were differentially expressed in the high- and low- groups in KIRC.

Conclusion: Our analysis showed that the central regulatory gene of cuproptosis, , has differential expression and modification levels in various tumors, which is associated with cellular function, immune modulation, and disease prognosis. Thus, -dependent cuproptosis may serve as a brand-new target in future therapeutic approaches against tumors.