Frontiers in Pharmacology (Feb 2025)
Zebularine showed anti-tumor efficacy in clear cell renal cell carcinoma
Abstract
BackgroundClear cell renal cell carcinoma (ccRCC) has the highest morbidity among renal cell carcinoma (RCC) subtypes. While existing clinical pharmacological intervention strategies have achieved certain efficacy, challenges including inevitable drug resistance and intricate immune heterogeneity of ccRCC continue to hinder their biomedical application. Therefore, developing novel immunotherapeutic agents and identifying patients who can gain the greatest benefits from these therapies are urgent issues.MethodsTo address these challenges, mRNA expression profile and clinical data of ccRCC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. These data were integrated and randomly allocated into training and test sets. Immune-related differentially expressed genes (IRDEGs) were used to construct an immune-related gene prognostic index (IRGPI). Both prognostic performance metrics and immune phenotyping were employed to evaluate the effectiveness of the model. Furthermore, model IRDEGs (mIRDEGs) in two risk subgroups were leveraged to select potential therapeutic compounds. Afterwards, network pharmacology and molecular docking techniques were used to elucidate the anti-cancer mechanisms of Zebularine (Zeb). Finally, the anti-cancer efficacy of Zeb was validated through in vivo and in vitro experiments.ResultsOur constructed IRGPI exhibited superior prognostic performance. The drug screening revealed Zeb potentially targets the PI3K-Akt signaling pathway to exert its anti-cancer effects. Subsequent experimental validation corroborated these theoretical findings.ConclusionThis study presents a prognostic model to evaluate immune cell infiltration and predict the prognosis of ccRCC patients. The identified small molecule compound provides a novel therapeutic avenue for treating ccRCC patients.
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