Abstract

Summary Renal cell carcinoma (RCC) is highly vascular and prone to venous invasion and tumor thrombus (TT) formation, though its underlying molecular mechanisms remain unclear. In this study, we found suprabasin ( SBSN ) was upregulated in RCC and enriched in TT, associated with poor prognosis. SBSN promoted RCC cell proliferation, migration, and invasion via the NF-κB-CD44 axis, and its knockdown inhibited tumor growth and affected epithelial-mesenchymal transition in vivo . Clinically, SBSN expression in RCC tissue positively correlates with microvessel density. Mechanistically, SBSN drove angiogenesis paracrinally by upregulating interferon alpha-inducible protein 6 ( IFI6 ) in endothelial cells, which in turn inhibits endothelial cell apoptosis and promotes tube formation. Collectively, SBSN acts both intrinsically (NF-κB-CD44 axis) to boost tumor aggressiveness and extrinsically (SBSN-IFI6 axis) to promote angiogenesis. This study positions SBSN as a potential prognostic biomarker and therapeutic target to disrupt both tumor growth and vascular support in advanced RCC.