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.
