Testicular torsion is a serious emergency and a well-known cause of male infertility. It represents 10 %–15 % of scrotal diseases in children. Kisspeptin (KISS1) is a hormone secreted from the hypothalamic nuclei and testis, but its role in testis is not fully understood. Semaglutide is a novel antidiabetic glucagon-like peptide 1 (GLP-1) analog. Hence, we designed the current study to elucidate the possible ameliorative effect of semaglutide on ischemia/reperfusion-induced testicular dysfunction in rats and highlight the role of the testicular GLP-1/PCG-1α–PPAR-α–KISS1 signaling pathway. We randomly divided 50 male Sprague Dawley into five equal groups (10 rats each): SHAM, exendin 9-39 -treated (EX), testicular torsion/detorsion (T/D), testicular torsion/detorsion and semaglutide-treated (SEM + T/D), and testicular torsion/detorsion, exendin, and semaglutide-treated (EX + SEM + T/D). We quantified serum follicle-stimulating hormone, luteinizing hormone, total testosterone, testicular oxidative stress markers, testicular gene expression of GLP-1/KISS1 pathway-related genes (KISS1, KISS1R, GLP-1, GLP-1R, PGC-1α, PPAR-α), steroidogenesis pathway-related genes (STAR, CYP11A1, CYP17A1, HSD17B3, CYP19A1), HO-1, Nrf-2, and testicular protein expression of HIF-1α, TNF-α, NF-κβ, Caspase-3, FAS, proliferating cell nuclear antigen, and KISS1 through testicular histopathology and immunohistochemistry assays. Testicular torsion/detorsion markedly elevated proapoptotic, proinflammatory, and oxidative stress marker levels, noticeably downregulating the expression of GLP-1/KISS1 and steroidogenesis pathway-related proteins. Semaglutide administration significantly ameliorated all these deleterious effects. Nevertheless, injecting exendin, a GLP1-R antagonist, before semaglutide abolished all the documented improvements. We concluded that semaglutide ameliorated ischemia/reperfusion-induced testicular dysfunction by modulating the GLP-1/PGC-1α–PPAR-α/KISS1/steroidogenesis signaling pathway, improving testicular oxidative state, and suppressing testicular inflammation and apoptosis.

睾丸扭转是一种严重的紧急情况，也是男性不育的众所周知的原因。它占儿童阴囊疾病的 10%–15%。Kisspeptin (KISS1) 是一种由下丘脑核和睾丸分泌的激素，但其在睾丸中的作用尚不完全清楚。Semaglutide 是一种新型抗糖尿病胰高血糖素样肽 1 (GLP-1) 类似物。因此，我们设计本研究是为了阐明索马鲁肽对缺血/再灌注引起的大鼠睾丸功能障碍可能的改善作用，并强调睾丸 GLP-1/PCG-1α-PPAR-α-KISS1 信号通路的作用。我们将 50 只雄性 Sprague Dawley 随机分为 5 个相等的组（每组 10 只）：SHAM、exendin 9-39 治疗组 (EX)、睾丸扭转/扭转组 (T/D)、睾丸扭转/扭转组和索马鲁肽治疗组 (SEM + T/D) 和睾丸扭转/扭转、毒蜥外泌肽和索马鲁肽治疗 (EX + SEM + T/D)。我们量化了血清卵泡刺激素、黄体生成素、总睾酮、睾丸氧化应激标记物、GLP-1/KISS1 通路相关基因（KISS1、KISS1R、GLP-1、GLP-1R、PGC - 1α、PPAR）的睾丸基因表达。 -α )、类固醇生成途径相关基因 ( STAR、CYP11A1、CYP17A1、HSD17B3、CYP19A1 )、HO-1、Nrf-2以及 HIF-1α、TNF-α、NF-κβ、Caspase-3 的睾丸蛋白表达，通过睾丸组织病理学和免疫组织化学分析检测 FAS、增殖细胞核抗原和 KISS1。睾丸扭转/扭转显着升高促凋亡、促炎症和氧化应激标志物水平，显着下调 GLP-1/KISS1 和类固醇生成途径相关蛋白的表达。索马鲁肽给药显着改善了所有这些有害作用。然而，在索马鲁肽之前注射 Exendin（一种 GLP1-R 拮抗剂）消除了所有记录的改善。我们的结论是，索马鲁肽通过调节 GLP-1/PGC-1α-PPAR-α/KISS1/类固醇生成信号通路、改善睾丸氧化状态、抑制睾丸炎症和细胞凋亡来改善缺血/再灌注引起的睾丸功能障碍。