MULTI-COHORT TRANSCRIPTOMIC ANALYSIS REVEALS SHARED INFLAMMATORY SIGNALING AND UROTHELIAL DYSFUNCTION ACROSS IC/BPS PHENOTYPES

Abstract

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a heterogeneous disorder characterized by bladder pain, inflammation, and urothelial dysfunction, yet the molecular features shared across clinically defined disease phenotypes remain incompletely understood. Toll-like receptor 4 (TLR4) and acyloxyacyl hydrolase (AOAH), a regulator of TLR4 ligand activity, have been implicated in IC/BPS in clinical and preclinical mechanistic studies. Here, we performed a multi-cohort reanalysis of four independent human IC/BPS transcriptomic datasets spanning bladder tissue and urine sediment from non-ulcer/non-Hunner, ulcerative/Hunner, normal-capacity, low-capacity, non-lesion, and lesion phenotypes. We evaluated immune cell-associated expression, urothelial differentiation and barrier integrity, TLR4 and pro-inflammatory signaling, and AOAH expression. IC/BPS exhibited phenotype-specific immune remodeling, yet shared features were also identified. Bladder-tissue IC/BPS was consistently associated with reduced expression of urothelial differentiation and barrier markers, together with increased TLR4 recognition and pro-inflammatory signaling. AOAH expression was elevated across all three bladder-tissue cohorts and was associated with monocyte/macrophage and pro-inflammatory transcriptional states. TLR4 signaling similarly paralleled myeloid and inflammatory features, whereas inflammatory programs generally showed inverse relationships with urothelial barrier markers. Notably, independently defined severe phenotypes of ulcerative IC and low-capacity IC showed concordant molecular remodeling characterized by increased leukocyte and monocyte/macrophage signatures, enhanced TLR4 signaling, elevated AOAH expression, and reduced urothelial barrier-associated expression. Together, these findings identify reproducible molecular signatures that extend across IC/BPS phenotypes and support a model in which urothelial dysfunction and TLR4-AOAH-associated myeloid inflammatory states coexist across disease phenotypes. These results provide a molecular framework for stratifying IC/BPS beyond clinical labels and identify shared and subtype-specific molecular signatures that may inform therapeutic response evaluation and clinical management.