Therapeutic potential of hesperidin in diabetes mellitus‐induced erectile dysfunction through Nrf2‐mediated ferroptosis and oxidative stress

Abstract Background Among erectile dysfunction (ED) caused by metabolic abnormalities, diabetes mellitus‐induced ED (DMED) progresses rapidly, manifests with severe symptoms, and shows reduced responsiveness to conventional medications. Hyperglycemia in the corpus cavernosum has been linked to the induction of both ferroptosis and oxidative stress, which are mediated by nuclear factor E2 related factor 2 (Nrf2). Hesperidin (Hes), a flavonoid compound, has been revealed to activate Nrf2 in certain diabetic complications, yet the efficacy of Hes on DMED and the specific mechanism remain unclear. Objectives To elucidate the potential mechanism and efficacy of Hes in regulating Nrf2‐mediated ferroptosis and oxidative stress in DMED. Materials and methods DMED rats were constructed through the intraperitoneal injection of streptozotocin (STZ), partially supplemented with Hes. In parallel, in vitro research utilized human umbilical vein endothelial cells (HUVECs), with glucose addition to simulating a high glucose (HG) environment, and induced with Hes or ML385 (an Nrf2 inhibitor). Penile tissues and HUVECs were harvested for subsequent analyses. Results The results of this study indicate that Hes partially reversed the impaired erectile function. The expression of Nrf2, glutathione peroxidase 4 (GPX4), and heme oxygenase‐1 (HO‐1) in the corpus cavernosum elevated after supplementing with Hes, resulted in an inhibition in ferroptosis and oxidative stress. Moreover, the quantity and function of erectile effector cells were restored, and cavernous fibrosis was ameliorated. In HG‐induced HUVECs, Hes ameliorated Nrf2‐mediated ferroptosis and oxidative stress, effects which ML385 partially reversed. Conclusions Hes exerts a therapeutic effect on DMED rats and a regulatory mechanism on the Nrf2–HO‐1/GPX4 axis, concurrently revitalizing endothelial and smooth muscle cells, and diminishing fibrosis. Our study provides robust preclinical evidence for employing Hes in treating DMED.