Targeting STING alleviates pyroptosis of bladder epithelial cells and ameliorates bladder fibrosis in neurogenic bladder

Neurogenic bladder (NB) is a common urinary system disease in children and often accompanied by bladder inflammation and fibrosis. Currently, NB has very few treatment options. Stimulator of interferon genes (STING) links immune response with inflammatory processes and is associated with the development of diverse fibrotic diseases. However, the regulatory role of STING in NB-induced bladder fibrosis remains unclear. In this study, we established the NB rat model by transecting the L6-S1 spinal nerves. RNA Sequencing and correlation analysis indicated that activation of the cGAS-STING pathway and the Pyroptosis related NLRP3 pathway occurred in the fibrotic bladder. Further research indicated that after STING activation, it would activate downstream targets such as interferon regulatory transcription factor 3 (IRF3) and NF-κB, induce Pyroptosis in bladder epithelial cells, and ultimately lead to the generation of pro-inflammatory and fibrotic factors. Intravesical C-176 (a STING inhibitor) treatment remarkably decreased the Collagen content and improved bladder function. In addition, our study also elucidated that MFN2 affected the release of mtDNA by binding to Bax and regulated the cGAS-STING pathway. In conclusion, our research verified that the MFN2-BAX/cGAS-STING/NLRP3 axis as a critical driver of NB-induced bladder fibrosis. Targeting STING provides a novel therapeutic strategy to reduce inflammation and fibrosis, with potential clinical applications for NB management.

Fibrosis; Inflammation; Neurogenic bladder; Pyroptosis; STING.