Molecular Signatures of Bladder Pain Syndrome: A Systematic Review Towards Phenotype-Informed Diagnostics

Bladder painsyndrome (BPS) is a disabling condition diagnosed clinically, characterised by marked heterogeneity in cystoscopic phenotype and treatment response. Molecular mechanisms remain incompletely defined, and no validated biomarkers currently support diagnosis or phenotypic stratification. The objective was to synthesise molecular evidence underpinning BPS and evaluate biomarker candidates relevant to phenotype-informed diagnostics.

A Preferred Reporting Items for Systematic reviews and Meta-Analyses-guided search of PubMed and the Cochrane Library (to 24 November 2024) identified human and experimental studies reporting molecular, transcriptomic, proteomic or biochemical characterisation of BPS (including studies indexed under interstitial cystitis). Eligibility followed the SPIDER framework. Owing to heterogeneity in phenotyping, biospecimens and analytical platforms, findings were narratively synthesised and organised by mechanistic domain.

Twenty studies were included (316 records screened). Convergent findings supported four inter-related domains: immune activation and lymphoid recruitment, including IL6, TNF, CXCL13/CXCR5 and IL17RA-linked signalling; urothelial barrier impairment with reduced CDH1 and TJP1 and increased adhesion molecules (e.g. ICAM1); neurogenic sensitisation involving NGF, ADCYAP1 and CNR1; and inflammasome and oxidative pathways, including NLRP3, IL1B and NOS2. Where phenotypes were distinguished, Hunner-type BPS demonstrated an immune- and endoplasmic-reticulum-stress-enriched profile compared with non-Hunner disease. Across studies, biomarker signals showed limited reproducibility, constrained by small cohorts and inconsistent phenotyping.

Current evidence supports BPS as a syndrome comprising biologically distinct endotypes spanning immune, epithelial, neurogenic and inflammasome pathways. Large, rigorously phenotyped human studies using harmonised multi-omics approaches are required to validate biomarkers and enable phenotype-informed diagnosis and targeted therapy.