ROCK2 promotes renal cell carcinoma progression by functioning as an RNA-binding protein regulating the PAI-1/NLRP3 axis and senescence escape

Renal cell carcinoma (RCC) is an aggressive malignancy with limited treatment options at advanced stages. Although the incidence of RCC is increasing globally, the molecular mechanisms driving its progression remain poorly understood. In this study, we demonstrate that ROCK2 promotes RCC progression through post-transcriptional regulation of PAI-1. RNA sequencing and cytokine profiling of ROCK2-knockdown RCC cells revealed a significant decrease in PAI-1 expression. Overexpression of PAI-1 restored NLRP3 inflammasome activation, inhibited cellular senescence, and enhanced mitochondrial fission and autophagy, effects that were abolished by the NLRP3 inhibitor MCC950. In vivo, PAI-1 overexpression promoted tumor growth and suppressed both apoptosis and senescence, while NLRP3 inhibition reversed these effects. RNA immunoprecipitation assays confirmed that ROCK2 directly binds to PAI-1 mRNA, suggesting a post-transcriptional regulatory mechanism. Collectively, these results support a model in which ROCK2 facilitates RCC progression by stabilizing PAI-1 mRNA, thereby activating the NLRP3 inflammasome, inhibiting cellular senescence, and promoting mitochondrial remodeling, suggesting that the ROCK2/PAI-1/NLRP3 axis may serve as a potential therapeutic target for RCC.