SPHK1/S1PR1/PPAR-α axis restores TJs between uroepithelium providing new ideas for IC/BPS treatment

Interstitial cystitis/bladder pain syndrome (IC/BPS) represents a chronic, aseptic inflammatory bladder condition with an unclear etiology and few therapeutic options. A composite barrier structure composed of the uroepithelium and glycosaminoglycan layer forms on the bladder’s inner surface to block urine and other harmful substances. Dysfunction of this barrier may initiate the pathogenesis of IC/BPS. Sphingosine-1-phosphate (S1P) plays a crucial role in forming tight junctions. Perfusion of S1P into the bladder restored uroepithelial tight junctions in mice with cyclophosphamide-induced acute cystitis and ameliorated symptoms of the lower urinary tract. Mice lacking sphingosine kinase 1 (SHPK1) exhibited more severe bladder injuries and dysfunction. Concurrent in vitro experiments elucidated S1P’s protective effects and its role as a primary messenger through SPHK1 and S1P receptor 1 (S1PR1) knockdown. This study identifies a novel mechanism whereby S1P binding to S1PR1 activates the PPAR-α pathway, thereby enhancing cholesterol transport and restoring tight junctions between uroepithelial cells. These findings elucidate the regulatory role of S1P in the bladder epithelial barrier and highlight a promising therapeutic target for IC/BPS.