A Novel Flavonoid Derivative of Icariside II (YS-10) Improves Erectile Dysfunction in a Diabetic Rat Model by Inhibiting Ferroptosis via Activation of the Nrf2/HO-1/GPX4 Pathway

Yang Liu,1,2 Guan-nan Liu,1,2 Ya-rong Zha,1 Chen-li Pan,1 Yong-de Xu,3 Hong-wei Li,1 Yue-yue Zang,1 Wan-qi Wang,1 Jun-jie Yao,1 Jun-tao Sun,1,2 Yong Yang,2 Zhi-tao Wei2 1Changchun University of Chinese Medicine, Changchun, Jilin Province, People’s Republic of China; 2Department of Urology, The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin Province, People’s Republic of China; 3Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People’s Republic of ChinaCorrespondence: Yong Yang, Department of Urology, The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin Province, 130021, People’s Republic of China, Email [email protected] Zhi-tao Wei, Department of Urology, The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin Province, 130021, People’s Republic of China, Email [email protected]: This study aimed to evaluate the therapeutic potential of YS-10, a novel flavonoid derivative of icariside II (ICA II), and to explore its mechanism of action in a diabetic rat model of erectile dysfunction (DMED).Methods: Twenty-four male Sprague-Dawley rats were divided into four groups: control, DMED, DMED + ICA II (2.5 mg/kg/day), and DMED + YS-10 (2.5 mg/kg/day). Treatments lasted for 4 weeks followed by a 3-day washout. Erectile function was assessed, and penile tissues were analyzed by histology, immunohistochemistry, ELISA, and Western blot. In vitro, primary corpus cavernosum endothelial cells (CCECs) were treated with advanced glycation end products (AGEs), YS-10, Fer-1 (ferroptosis inhibitor), or ML385 (Nrf2 inhibitor) to evaluate oxidative stress and ferroptosis.Results: In vivo, both YS-10 and ICA II (2.5 mg/kg/day) significantly improved erectile function in diabetic rats, increased smooth muscle content, reduced collagen deposition, and enhanced endothelial marker (CD31) expression in penile tissue (p < 0.01 vs DMED group). The maximum ICP/MAP ratio and oxidative stress markers were similarly restored in both treatment groups, with no significant difference between YS-10 and ICA II (p > 0.05). In vitro, YS-10 reversed AGEs-induced injury and ferroptosis in corpus cavernosum endothelial cells (CCECs), upregulated GPX4, downregulated ACSL4, and reduced ROS and lipid peroxidation, comparable to the effects of the ferroptosis inhibitor Fer-1. YS-10 also promoted Nrf2 nuclear translocation and elevated HO-1 expression. Molecular docking, immunofluorescence, and Western blotconfirmed the interaction between YS-10 and the Nrf2/HO-1/GPX4 signaling pathway.Conclusion: YS-10 improves erectile function in diabetic rats by reducing oxidative stress and inhibiting ferroptosis via activation of the Nrf2/HO-1/GPX4 pathway. At 2.5 mg/kg/day, YS-10 was effective, well-tolerated, and showed efficacy comparable to ICA II. These findings support its potential as a promising candidate for diabetes-related erectile dysfunction therapy.Keywords: diabetes mellitus, erectile dysfunction, ferroptosis, YS-10, ICA II, Nrf2, GPX4