El Sayed Nermein F, Baraka Sara A, El-Mokadem Bassant M, El Osaily Heba H, Bishr Abeer
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ahram Canadian University, Cairo, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ahram Canadian University, Cairo, Egypt.
J Pharmacol Exp Ther. 2025 Jun 11;392(8):103629. doi: 10.1016/j.jpet.2025.103629.
Semaglutide (Sema), a potent glucagon-like peptide-1 receptor agonist, is widely used in the management of type 2 diabetes mellitus due to its glucose-lowering effects. Beyond this, Sema also exhibits antioxidative, anti-inflammatory, antiapoptotic, and autophagy-enhancing properties. However, its potential role against 5-fluorouracil (5-FU)-induced hepatic injury has not yet been investigated. Hence, our study aims to investigate the hepatoprotective role of Sema against 5-FU-induced hepatotoxicity. Rats were randomly distributed in 5 groups: group I was the control group (saline only); group II and the rest of the groups except the normal group received 5-FU (150 mg/kg i.p.) to induce hepatotoxicity; group III received Sema (0.3 mg/kg orally) + 5-FU; group IV received Sema + 5-FU + chloroquine (CQ; 10 mg/kg i.p., 10 minutes prior to 5-FU);group V received 5-FU + CQ. Our results showed that 5-FU markedly increased hepatic enzyme levels, oxidative stress, inflammatory markers, and histological injury. However, pretreatment with Sema effectively counteracted these harmful effects by suppressing the reactive oxygen species/NF-κB/NLRP3 inflammasome pathway and enhancing PINK1/Parkin-mediated mitophagy. Notably, the addition of CQ, an autophagy inhibitor, abolished the protective role of Sema in autophagic flux. Furthermore, Sema reduced proinflammatory cytokines (tumor necrosis factor-α and interleukin-6), oxidative stress markers (malondialdehyde), and apoptotic markers (caspase-3), enhanced the antioxidant activity (glutathione), and promoted the activation of the phosphorylated CREB/Nrf2/HO-1 signaling pathway. In conclusion, Sema attenuates the 5-FU-induced liver injury through a multifaceted mechanism involving suppression of inflammation, oxidative stress, and apoptosis, as well as by increasing autophagic flux by inducing the phosphorylated CREB/PINK/Parkin trajectory pathway. These findings suggest that Sema holds promise as a novel therapeutic approach for preventing chemotherapy-induced liver toxicity. SIGNIFICANCE STATEMENT: Semaglutide, a GLP-1 receptor agonist, significantly mitigates 5-fluorouracil-induced hepatotoxicity in rats, suppressing the reactive oxygen species/NF-κB/NLRP3 inflammasome pathway and reducing oxidative stress and inflammation. Semaglutide also enhances mitophagy by activating the phosphorylated CREB/PINK1/Parkin pathway, aiding in the clearance of damaged mitochondria, confirmed using chloroquine, an autophagy inhibitor.
司美格鲁肽（Sema）是一种强效胰高血糖素样肽-1受体激动剂，因其降血糖作用而广泛用于2型糖尿病的治疗。除此之外，司美格鲁肽还具有抗氧化、抗炎、抗凋亡和增强自噬的特性。然而，其对5-氟尿嘧啶（5-FU）诱导的肝损伤的潜在作用尚未得到研究。因此，我们的研究旨在探讨司美格鲁肽对5-FU诱导的肝毒性的肝保护作用。将大鼠随机分为5组：第一组为对照组（仅给予生理盐水）；第二组和除正常组外的其他组接受5-FU（150mg/kg腹腔注射）以诱导肝毒性；第三组接受司美格鲁肽（0.3mg/kg口服）+5-FU；第四组接受司美格鲁肽+5-FU+氯喹（CQ；10mg/kg腹腔注射，在5-FU前10分钟给药）；第五组接受5-FU+CQ。我们的结果表明，5-FU显著升高了肝酶水平、氧化应激、炎症标志物和组织学损伤。然而，司美格鲁肽预处理通过抑制活性氧/NF-κB/NLRP3炎性小体途径并增强PINK1/Parkin介导的线粒体自噬有效地抵消了这些有害影响。值得注意的是，添加自噬抑制剂CQ消除了司美格鲁肽在自噬流中的保护作用。此外，司美格鲁肽降低了促炎细胞因子（肿瘤坏死因子-α和白细胞介素-6）、氧化应激标志物（丙二醛）和凋亡标志物（半胱天冬酶-3），增强了抗氧化活性（谷胱甘肽），并促进了磷酸化CREB/Nrf2/HO-1信号通路的激活。总之，司美格鲁肽通过多方面机制减轻5-FU诱导的肝损伤，该机制包括抑制炎症、氧化应激和凋亡，以及通过诱导磷酸化CREB/PINK/Parkin轨迹途径增加自噬流。这些发现表明，司美格鲁肽有望成为预防化疗诱导的肝毒性的一种新的治疗方法。意义声明：胰高血糖素样肽-1受体激动剂司美格鲁肽显著减轻大鼠5-氟尿嘧啶诱导的肝毒性，抑制活性氧/NF-κB/NLRP3炎性小体途径并减轻氧化应激和炎症。司美格鲁肽还通过激活磷酸化CREB/PINK1/Parkin途径增强线粒体自噬，有助于清除受损线粒体，这一作用通过自噬抑制剂氯喹得到证实。
