AbstractPurposeTo explore an efficient preventive strategy for radiation cystitis.MethodsWe instilled IR‐780 into the bladders of rats 1 h before bladder irradiation, and its bio‐distribution was observed at different times. Bladders were then examined for pathogenic alterations and inflammation levels by day 3 and week 12 postirradiation, and the functional characteristics of the bladder were tested via cystometry by week 12. Human uroepithelial sv‐huc‐1 cells were used to determine the effect of IR‐780 on cell viability, regardless of irradiation. We measured the intracellular levels of oxidative stress, DNA damage, apoptosis proportion, and the expression of antioxidant proteases and apoptotic caspases in IR‐780 pretreated cells after radiation.ResultsIR‐780 is localized in the urothelium after intravesical instillation in vivo. Ionizing radiation could induce acute impairment of the bladder urothelium and inflammation in the bladder on day 3. Fibrosis of the irradiated bladder progressed and eventually affected voiding function at 12 weeks. Treatment with IR‐780 before irradiation ameliorated these changes. In vitro, IR‐780 protected against cell viability and apoptosis of sv‐huc‐1 cells after irradiation. Additionally, IR‐780 may assist in eliminating reactive oxygen species and repairing irradiation‐induced DNA damage.ConclusionOur data indicate that IR‐780 can be used before irradiation to prevent acute urinary mucosal injury and late bladder dysfunction. Moreover, early urothelial impairment plays a significant role in radiation cystitis development.