Pharmacological modulation of STING-associated signaling alleviates bladder inflammation, epithelial barrier...

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic inflammatory disorder characterized by urothelial barrier disruption, neurogenic inflammation, and persistent pelvic pain. However, the upstream molecular mechanisms linking epithelial dysfunction with inflammatory and vascular alterations remain incompletely understood. In this study, we investigated the involvement of STING-associated signaling in experimental cystitis and evaluated the therapeutic potential of the anti-inflammatory marine-derived briareane diterpenoid excavatolide B (EXCB) and its derivative EXCB79 in a cyclophosphamide (CYP)-induced rat model. CYP-induced cystitis was accompanied by increased immunoreactivity of STING together with elevated TBK1 and NF-κB immunostaining, urothelial barrier disruption, CD11b⁺ myeloid cell infiltration, increased expression of the inflammatory mediators COX-2 and IL-1β, angiogenesis-associated changes, and enhanced pelvic hypersensitivity. At the concentrations selected for subsequent analyses, EXCB (20 µg/mL) and EXCB79 (5 µg/mL) attenuated pelvic hypersensitivity and were associated with reduced bladder inflammation and partial preservation of epithelial barrier integrity. Double immunofluorescence analysis demonstrated altered spatial associations between STING and CD11b, CD31, VEGF, ZO-1, E-cadherin, and vimentin following CYP administration. Pharmacological modulation of STING-associated signaling was accompanied by reduced immunoreactivity of STING-associated markers together with attenuation of inflammatory, vascular, and epithelial barrier-related alterations, including reduced VEGF immunoreactivity. Collectively, these findings support an association between STING-associated signaling and inflammatory, vascular, and epithelial alterations in experimental cystitis and suggest that pharmacological modulation of this pathway may represent a potential therapeutic strategy for bladder inflammation and pain-related symptoms.