Single-Cell RNA Sequencing Identifies Conserved Crosstalk and Core Shared Differentially Expressed Genes in Clear Cell Renal Cell Carcinoma and Obesity.

Objective: Obesity is a well-established modifiable risk factor for clear cell renal cell carcinoma (ccRCC), yet the cellular and molecular crosstalk between obesity and ccRCC remains poorly defined. Single-cell RNA sequencing (scRNA-seq) enables high-resolution characterization of cellular heterogeneity, providing a robust strategy to dissect conserved pathological mechanisms linking the two disorders.

Methods: scRNA-seq was performed to profile cellular composition and transcriptional patterns in ccRCC/normal renal tissues and obese/lean adipose tissues. Shared differentially expressed genes (DEGs) were identified and functionally enriched. Independent bulk RNA-seq datasets were used to validate core cross-disease DEGs. Protein-protein interaction (PPI) networks were constructed, and drug-gene interaction analysis was conducted to screen repurposing candidates.

Results: Convergent cellular remodeling was identified in ccRCC and obese tissues. Adipocytes, immune cells, and stromal cells served as conserved core regulatory hubs. A total of 19 validated core DEGs formed a PPI network enriched in immune activation and inflammation, with cytokine-cytokine receptor interactions and chemokine signaling being dominant. Multiple FDA-approved drugs were predicted for comorbidity-targeted repurposing.

Discussion: Obesity-driven chronic inflammatory dysregulation serves as a key mechanistic link promoting ccRCC development and progression, revealing the intrinsic connection between obesity and ccRCC.

Conclusion: This study delineates conserved cellular and molecular mechanisms underlying the obesity-ccRCC association. The 19 core DEGs represent critical cross-disease targets, and the identified repurposable drugs provide actionable strategies for managing ccRCC-obesity comorbidity.