Survivin drives renal cell carcinoma tumorigenesis via proliferative and metabolic adaptation.

Renal cell carcinoma (RCC) is a heterogeneous malignancy for which clear cell RCC (ccRCC) represents the most common and clinically aggressive subtype. Survivin (encoded by BIRC5), an inhibitor of apoptosis and key regulator of mitosis, is frequently overexpressed in RCC and associated with poor prognosis, yet its broader role in kidney cancer biology remains poorly defined. By analyzing transcriptomic data from The Cancer Genome Atlas-kidney renal clear cell carcinoma (TCGA-KIRC) cohort, we found that advanced-stage ccRCC exhibits widespread dysregulation of cell-cycle pathways, with 15,160 genes upregulated and 479 genes downregulated in stage IV compared to stage I tumors. To define survivin's functional contribution, we performed loss-of-function and pharmacologic inhibition studies in murine RENCA and human 786-O RCC cell lines. Survivin knockdown or treatment with the small-molecule inhibitor YM155 reduced proliferation, S-phase entry and cyclin D1 expression, and impaired collective (wound-healing), single-cell and transwell migration. Unexpectedly, survivin depletion increased mitochondrial content while lowering oxygen consumption, indicating accumulation of dysfunctional mitochondria. Together, these findings identify survivin as a node between cell-cycle progression and mitochondria in RCC.