circTNS3 accelerates bladder outlet obstruction-induced bladder remodeling by amplifying cGAS-STING signaling via the miR-510-5p/cGAS axis

Abstract Background Bladder outlet obstruction (BOO) induces progressive bladder remodeling through sustained intravesical pressure overload, leading to structural and functional impairment. Circular RNAs (circRNAs) play critical regulatory roles in diverse physiological and pathological processes. However, the functions of circRNAs in BOO-induced bladder remodeling remain poorly understood. Methods We established a rat BOO model and induced circTNS3 overexpression via intradetrusor injection of an AAV9 vector. Bladder remodeling was assessed by histological and urodynamic analyses. The effect of circTNS3 on the apoptosis of bladder smooth muscle cells (BSMCs) was studied both in vivo and in vitro. Transcriptomic sequencing, bioinformatics analysis, and dual-luciferase reporter assays were performed to elucidate the molecular mechanisms regulated by circTNS3. Results We identified circTNS3 as an evolutionarily conserved circRNA that was significantly downregulated in BOO bladder tissues and experimentally validated its circular structure and cytoplasmic localization in human BSMCs. circTNS3 overexpression accelerated progression toward a decompensated bladder phenotype in BOO rats and promoted apoptosis of BSMCs in vivo and in vitro, as indicated by increased cleaved caspase-3 expression and TUNEL positivity. Hypoxia induced mitochondrial oxidative stress and increased cytosolic mitochondrial DNA levels in human BSMCs, accompanied by activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. circTNS3 functioned as a competing endogenous RNA to sequester miR-510-5p, thereby relieving its repression of cGAS and amplifying cGAS-STING signaling. Notably, the pro-apoptotic effect of circTNS3 was partially attenuated by RU.521, a selective cGAS inhibitor. Conclusions circTNS3 amplifies the miR-510-5p/cGAS-STING signaling axis and promotes apoptosis of BSMCs, thereby contributing to progression toward bladder decompensation during BOO. These findings highlight this regulatory network as a potential therapeutic target for BOO-associated bladder remodeling.