Pharmacological therapy of diabetes mellitus-induced erectile dysfunction (DMED) is intractable owig to the poor response to phosphodiesterase type 5 inhibitors (PDE5i). The surge in the number of diabetic patients makes it extremely urgent to find a novel therapy for DMED. Ferroptosis is a recently discovered form of cell death evoked by lipid peroxidation and is related to several diabetic complications. GPX4, an important phospholipid hydroperoxidase, can alleviate ferroptosis and maintain redox balance via reducing lipid peroxides. However, whether GPX4 can be a prospective target of DMED needs to be determined. Fifty rats were randomly divided into control group, DMED group, DMED + negative control group (DMED + NC group), DMED + low-dose group (1 × 10⁶ infectious units), and DMED + high-dose group (2 × 10⁶ infectious units). Erectile function was assessed 4 weeks after intracavernous injection of GPX4 or negative control lentivirus. The penile shafts were collected for subsequent molecular biological and histological analysis. The results demonstrated that erectile function of the rats in DMED and DMED + NC groups was extremely impaired and was improved in a dose-dependent manner with GPX4 lentivirus (GPX4-LV) injection. Additionally, upregulation of the ACSL4-LPCAT3-LOX pathway, iron overload, oxidative stress, fibrosis, and decreased endothelial and smooth muscle cell numbers were observed in the corpus cavernosum of DMED group. Meanwhile, the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway was inhibited, and the Ras homolog gene family member A (RhoA)/Rho-associated protein kinase (ROCK) pathway was promoted in DMED rats. The above histologic alterations and related molecular changes were alleviated after GPX4-LV injection. The results revealed that GPX4 improved erectile function by modulating ferroptosis during DMED progression. This finding is of paramount significance in deciphering the molecular mechanism of hyperglycemia-induced ferroptosis, thereby providing a prospective target for preventing the development of DMED.

中文翻译：

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GPX4通过抑制铁死亡来缓解糖尿病引起的勃起功能障碍

糖尿病引起的勃起功能障碍 (DMED) 的药物治疗是对 5 型磷酸二酯酶抑制剂 (PDE5i) 反应不佳的棘手问题。糖尿病患者数量的激增使得寻找一种新的治疗 DMED 的方法变得极为紧迫。铁死亡是最近发现的一种由脂质过氧化引起的细胞死亡形式，与几种糖尿病并发症有关。GPX4 是一种重要的磷脂氢过氧化物酶，可通过减少脂质过氧化物来缓解铁死亡并维持氧化还原平衡。然而，GPX4 是否可以成为 DMED 的潜在目标尚待确定。50只大鼠随机分为对照组、DMED组、DMED+阴性对照组（DMED+NC组）、DMED+低剂量组（1×10 ⁶感染单位）和 DMED + 高剂量组（2 × 10 ⁶传染性单位）。在海绵体内注射 GPX4 或阴性对照慢病毒 4 周后评估勃起功能。收集阴茎干用于随后的分子生物学和组织学分析。结果表明，DMED 和 DMED + NC 组大鼠的勃起功能严重受损，并以剂量​​依赖性方式通过 GPX4 慢病毒 (GPX4-LV) 注射得到改善。此外，DMED 组的海绵体中观察到 ACSL4-LPCAT3-LOX 通路上调、铁过载、氧化应激、纤维化以及内皮细胞和平滑肌细胞数量减少。同时，DMED大鼠的一氧化氮（NO）/环磷酸鸟苷（cGMP）通路受到抑制，Ras同源基因家族成员A（RhoA）/Rho相关蛋白激酶（ROCK）通路得到促进。GPX4-LV注射后上述组织学改变和相关分子变化得到缓解。结果表明，GPX4 通过在 DMED 进展过程中调节铁死亡来改善勃起功能。这一发现对于破译高血糖诱导的铁死亡的分子机制具有重要意义，从而为预防DMED的发展提供了一个前瞻性的靶点。