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.