Sulforaphane activates Nrf2 to attenuate diabetic bladder dysfunction in a time-dependent manner

Diabetic bladder dysfunction (DBD) is a common and severe complication of diabetes mellitus, and there is a lack of effective interventions to slow its progression. This study aimed to investigate the critical role of the endogenous antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in the DBD, specifically within a type 1 diabetes mellitus (T1DM) model, and to validate whether its natural agonist, sulforaphane (SFN), exerts protective effects against the DBD by activating the Nrf2 pathway. Using a streptozotocin (STZ)-induced T1DM mouse model alongside Nrf2 knockout (Nrf2-KO) mice, this study systematically investigated the therapeutic role of SFN and its Nrf2-dependent mechanisms during both the compensatory and decompensatory stages of the DBD. In wild-type T1DM mice, SFN treatment significantly improved voiding function and suppressed bladder oxidative stress, inflammation, fibrosis, and apoptosis. However, all the protective effects of SFN were abolished in Nrf2-KO T1DM mice. Mechanistic studies demonstrated that SFN specifically activated Nrf2 and its downstream target genes, HO-1 and NQO1, in bladder tissue. This study confirms that Nrf2 activation plays a central role in delaying DBD progression. SFN protects the bladder protection by directly activating the Nrf2 signaling pathway and enhancing downstream antioxidant defenses, providing a new theoretical basis and potential therapeutic strategy for DBD management.