Quercetin alleviates radiation-induced erectile dysfunction by modulating oxidative stress and apoptosis through the Nrf2/HO-1 pathway.

BACKGROUND: Radiation-induced erectile dysfunction (Ri-ED) is a frequent and debilitating complication in male cancer patients undergoing pelvic radiotherapy, primarily driven by oxidative stress, endothelial injury, fibrosis, and apoptosis. Phosphodiesterase type 5 inhibitors show limited efficacy in Ri-ED because they depend on intact endothelial NO signalling. Quercetin, a naturally occurring flavonoid, possesses potent antioxidant, anti-apoptotic, and endothelial-protective properties; however, its role in Ri-ED and the underlying mechanisms remain insufficiently defined. METHODS: Thirty-two male Sprague-Dawley rats were randomly assigned to four groups (n = 8): Control, radiation-exposed model, low-dose quercetin (10 mg/kg/day) and high-dose quercetin (40 mg/kg/day). A single 20 Gy pelvic irradiation was delivered, followed by oral quercetin or vehicle for 28 days. Erectile function was evaluated by intracavernosal pressure to mean arterial pressure (ICPmax/MAP) ratio after cavernous nerve stimulation, and penile tissues were subjected to histology, immunohistochemistry, immunofluorescence, ELISA and Western blot to assess fibrosis, oxidative stress, apoptosis, endothelial/neuronal integrity and Nrf2/HO-1 signalling. In parallel, human umbilical vein endothelial cells (HUVECs) were exposed to 6 Gy irradiation with or without quercetin, and cell viability, intracellular ROS, and Nrf2/HO-1 expression and localisation were examined. RESULTS: Quercetin significantly improved erectile function in Ri-ED rats, partially restoring body weight, increasing ICPmax/MAP toward control levels, and partially normalizing erection frequency. Histological analyses showed that quercetin attenuated collagen accumulation, partially preserved cavernosal smooth muscle, and partially improved endothelial and neuronal marker expression (CD31, eNOS, NF, nNOS). Quercetin reduced ROS and MDA, partially restored SOD activity, increased NO and cGMP, and partially normalized Ca(2)⁺ levels, indicating a marked improvement in oxidative stress and NO/cGMP signalling. Apoptosis was alleviated by downregulating Bax, upregulating Bcl-2, and reducing the number of TUNEL-positive cells. At the molecular level, quercetin upregulated Nrf2 and HO-1 expression in penile tissue, as confirmed by immunofluorescence and Western blot. Consistently, in irradiated HUVECs, quercetin improved cell viability, decreased ROS accumulation, and enhanced Nrf2 and HO-1 expression with promotion of Nrf2 nuclear translocation, demonstrating direct endothelial protection via activation of the Nrf2/HO-1 pathway. CONCLUSION: Quercetin ameliorates Ri-ED by mitigating oxidative stress, fibrosis and apoptosis, preserving endothelial and neurovascular integrity, and activating the Nrf2/HO-1 signalling pathway in both penile tissue and endothelial cells. These findings provide experimental evidence supporting quercetin as a potential adjunct therapeutic agent for preventing or treating Ri-ED in patients undergoing pelvic radiotherapy.