Liu Yang, Liu Guan-Nan, Zha Ya-Rong, Pan Chen-Li, Xu Yong-de, Li Hong-Wei, Zang Yue-Yue, Wang Wan-Qi, Yao Jun-Jie, Sun Jun-Tao, Yang Yong, Wei Zhi-Tao
Changchun University of Chinese Medicine, Changchun, Jilin Province, People's Republic of China.
Department of Urology, The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin Province, People's Republic of China.
Drug Des Devel Ther. 2025 May 28;19:4481-4500. doi: 10.2147/DDDT.S518992. eCollection 2025.
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).
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.
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 ( < 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 ( > 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.
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.
本研究旨在评估淫羊藿次苷II（ICA II）的新型黄酮衍生物YS-10的治疗潜力，并在糖尿病性勃起功能障碍（DMED）大鼠模型中探讨其作用机制。
将24只雄性Sprague-Dawley大鼠分为四组：对照组、DMED组、DMED + ICA II（2.5 mg/kg/天）组和DMED + YS-10（2.5 mg/kg/天）组。治疗持续4周，随后有3天的洗脱期。评估勃起功能，并通过组织学、免疫组织化学、酶联免疫吸附测定（ELISA）和蛋白质免疫印迹法对阴茎组织进行分析。在体外，用晚期糖基化终产物（AGEs）、YS-10、Fer-1（铁死亡抑制剂）或ML385（Nrf2抑制剂）处理原代海绵体内皮细胞（CCECs），以评估氧化应激和铁死亡。
在体内，YS-10和ICA II（2.5 mg/kg/天）均显著改善糖尿病大鼠的勃起功能，增加平滑肌含量，减少胶原蛋白沉积，并增强阴茎组织中内皮标志物（CD31）的表达（与DMED组相比，P<0.01）。两个治疗组的最大阴茎海绵体内压/平均动脉压（ICP/MAP）比值和氧化应激标志物均得到类似恢复，YS-10和ICA II之间无显著差异（P>0.05）。在体外，YS-10可逆转AGEs诱导的海绵体内皮细胞（CCECs）损伤和铁死亡，上调谷胱甘肽过氧化物酶4（GPX4），下调长链脂酰辅酶A合成酶4（ACSL4），并减少活性氧（ROS）和脂质过氧化，其效果与铁死亡抑制剂Fer-1相当。YS-10还促进Nrf2核转位并提高血红素加氧酶-1（HO-1）的表达。分子对接、免疫荧光和蛋白质免疫印迹证实了YS-10与Nrf2/HO-1/GPX4信号通路之间的相互作用。
YS-10通过激活Nrf2/HO-1/GPX4途径减轻氧化应激并抑制铁死亡，从而改善糖尿病大鼠的勃起功能。在2.5 mg/kg/天的剂量下，YS-10有效且耐受性良好，其疗效与ICA II相当。这些发现支持其作为糖尿病相关性勃起功能障碍治疗的有前景候选药物的潜力。
