Resveratrol Alleviates Neurogenic Bladder Fibrosis and Urothelial Pyroptosis by Inhibiting the AKT/mTOR Signaling...

Neurogenic bladder (NB) is a debilitating urological disorder characterized by progressive bladder remodeling, fibrosis, and functional deterioration, yet effective mechanism-based therapies remain limited. The AKT/mTOR signaling pathway is a central regulator of cellular growth, inflammation, and tissue remodeling, but its contribution to NB pathogenesis remains incompletely understood. In this study, we established an NB rat model by bilateral L6-S1 spinal nerve transection and evaluated the therapeutic effects of resveratrol. Urodynamic and histological analyses showed that resveratrol reduced residual volume and pressure change, improved bladder compliance, attenuated bladder enlargement and fibrosis, and alleviated secondary renal injury. In addition, resveratrol partially restored β III Tubulin immunoreactivity and reduced pathological remodeling in both mucosal and muscular compartments of the bladder. Mechanistically, resveratrol suppressed epithelial-mesenchymal transition (EMT)-like changes, apoptosis, and pyroptosis, as reflected by restoration of E-cadherin, reduction of α-SMA, Bax, cleaved caspase-3, NLRP3, IL-1β, and Caspase-1, and decreased inflammatory cytokine production. These effects were accompanied by marked inhibition of AKT/mTOR/S6K signaling activation in vivo. Consistently, in vitro experiments showed that resveratrol protected urothelial cells from TGF-β1-induced injury, whereas pharmacological re-activation of mTOR with MHY1485 partially reversed its anti-fibrotic and anti-pyroptotic effects. Collectively, these findings indicate that resveratrol alleviates NB-associated bladder injury and fibrosis by inhibiting the AKT/mTOR/S6K signaling pathway, highlighting this pathway as a potential therapeutic target for NB.