Integrative Multi-Transcriptomic Uncovers Actionable Signatures and Drug Repurposing Candidates for ccRCC–Hypertension Comorbidity

Background: Hypertension is a common comorbidity and risk factor for clear cell renal cell carcinoma (ccRCC), yet the molecular mechanisms linking these two diseases remain unclear. This study aimed to investigate hypertension-related molecular signatures in ccRCC using integrated multi-transcriptomic analyses. Method: Hypertension-related differentially expressed genes (DEHRGs) in ccRCC were identified by integrating transcriptomic data from the TCGA-KIRC cohort with the GeneCards database. Functional enrichment, WGCNA, machine learning, GSVA, survival analysis, and Mendelian randomization were performed to identify and characterize hub genes. Spatial and single-cell transcriptomic analyses were used to investigate tumor heterogeneity and predict candidate therapeutic compounds, which were subsequently evaluated in vitro. Results: Four hypertension-related hub genes—SCNN1G, CASR, KCNJ1, and WNK4—were identified and were mainly involved in ion transport, electrolyte homeostasis, and blood pressure regulation. Diagnostic models based on these genes showed good discriminatory performance between tumor and normal tissues, and the nomogram showed good calibration and potential clinical benefit. Higher hypertension-related transcriptional activity was associated with significantly poorer overall survival, while MR analysis suggested a genetic association with ccRCC risk. Spatial transcriptomics revealed pronounced spatial heterogeneity of SCNN1G, CASR, KCNJ1, and WNK4, with these hub genes predominantly enriched in stromal and immune regions. Single-cell-based drug screening identified candidate compounds predicted to have antitumor activity, among which epicatechin gallate (ECG) and pseudoginsenoside-F11 showed favorable tumor selectivity. Conclusions: This study systematically characterized hypertension-related molecular signatures in ccRCC and identified SCNN1G, CASR, KCNJ1, and WNK4 as key hub genes. These genes may contribute to the molecular association between hypertension and ccRCC. They also represent promising candidate biomarkers and therapeutic targets. Integrated spatial and single-cell analyses further identified pseudoginsenoside-F11 and ECG as potential therapeutic compounds and supporting a potential molecular association between hypertension and ccRCC.