Pathophysiology and multi-target prevention strategies for cyclophosphamide-induced bladder injury.

Cyclophosphamide (CYP) is a cornerstone alkylating agent in oncology, autoimmune diseases, and hematopoietic stem cell transplantation, but its clinical use is often limited by bladder toxicity. This toxicity is primarily caused by acrolein, a reactive CYP metabolite that accumulates in urine and initiates urothelial injury. Barrier disruption allows toxicants to penetrate, amplifying oxidative stress, inflammation, neurogenic inflammation, and sensory sensitization. Persistent or severe damage can lead to detrusor dysfunction, interstitial remodeling, fibrosis, and a range of conditions, including hemorrhagic cystitis, interstitial cystitis/bladder pain syndrome (IC/BPS)-like symptoms, overactive bladder, and reduced compliance. Emerging strategies are being explored, such as natural products targeting redox-inflammasome pathways, mechanism-driven small molecules, drug repurposing, regenerative and barrier-repair approaches, and metabolic interventions. A stage-oriented, target-matched combination paradigm supported by biomarker profiling may enhance bladder protection, but preserving antitumor efficacy and generating robust clinical evidence are key translational requirements.