Unraveling the Therapeutic Potential of Scutellarin for Clear Cell Renal Cell Carcinoma: A Comprehensive Molecular Analysis.

BACKGROUND

Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma, is a significant global health issue. Despite advancements in surgery and systemic therapies, drug resistance remains a challenge, and more effective treatments are needed. Scutellarin, a natural flavonoid with anticancer properties, is a promising therapeutic option for ccRCC.

METHODS

This present study identified the potential target genes of scutellarin by searching four databases and utilized the TCGA-KIRC and GSE53757 datasets to identify ccRCC features genes. Protein-protein interaction networks and molecular complex detection analyses determined the hub genes through which scutellarin acts on ccRCC. Differential expression, receiver operating characteristic analysis, survival, and immune cell infiltration analyses were conducted successively on these hub genes in tumor and normal tissues to verify their clinical significance. The intracellular mechanism of the hub genes was explored using a single-cell dataset (GSE222703) to elucidate the intracellular pathway through which scutellarin exerts its anti-ccRCC effects. At last, molecular docking and molecular dynamics simulations were performed to confirm the stability of the receptor protein of the hub gene binding to scutellarin.

RESULTS

158 scutellarin targets were collected and identified through database searches. Analyzing the TCGA-KIRC and GSE53757 datasets separately identified finally 132 ccRCC feature genes through differential expression analysis and WGCNA. Protein-protein interaction network and molecular complex detection analyses revealed 26 hub genes potentially involved in key pathways of scutellarin in ccRCC. Differential expression analysis revealed significant differences in the expression of these hub genes between tumor and normal tissues. Receiver operating characteristic analysis demonstrated the fine diagnostic efficacy of these hub genes. Survival analysis indicated that the hub genes TYMS and CDCA2 were associated with a better prognosis, whereas the remaining hub genes had a poorer prognosis. Enrichment analysis revealed that hub genes mainly involved oxidative stress and cell cycle regulation. Single-cell RNA sequencing analysis suggested that most hub genes exert their effects on T helper cells. Molecular docking results showed stable docking of hub genes with scutellarin, except for SPAG5 and ASPM. Molecular dynamics simulations of the most stable docking sites, KIF20A, TYMS, and KIF18B, indicated stable complex formation compared with that of the internal reference protein GAPDH.

CONCLUSION

This integrated study provides a comprehensive analysis of the molecular targets and pathways affected by scutellarin in ccRCC. The identified hub genes and their related pathways present exciting prospects for therapeutic intervention and highlight the potential of scutellarin as a novel treatment for ccRCC. Additional research is necessary to investigate the precise molecular mechanisms and therapeutic advantages of scutellarin in preclinical and clinical contexts.