Urinary Biomarkers for Radiation Cystitis: Current Insights and Future Directions.

Radiation cystitis (RC) is a clinically challenging and often progressive complication of pelvic radiotherapy, marked by urothelial injury, vascular dysfunction, chronic inflammation, and fibrotic remodeling. Early diagnosis remains elusive due to nonspecific symptoms and the absence of validated molecular tools. As a biofluid in direct contact with the irradiated bladder, urine offers a unique molecular window into RC pathogenesis. In this review, we synthesize the current landscape of urinary biomarkers associated with the acute, latent, and chronic phases of RC, including inflammatory cytokines, oxidative stress products, epithelial injury markers, extracellular vesicles, microRNAs, proteomic signatures, and metabolomic alterations. We also integrate emerging mechanistic insights such as DNA damage responses, ROS generation, mitochondrial dysfunction, urothelial barrier disruption, senescence-associated secretory phenotypes, hypoxia-driven vascular injury, and profibrotic TGF-β signaling, all of which contribute to the release of urinary analytes. By linking phase-specific molecular pathways with corresponding urinary signatures, we highlight opportunities to leverage urine-based measurements for early detection, risk stratification, severity assessment, and therapeutic monitoring. A deeper understanding of the molecular mechanisms shaping urinary biomarker profiles will be essential for advancing precision diagnostics and improving long-term outcomes for patients with radiation cystitis.