Repurposing of semaglutide by targeting SIRT1 and TGF-β/Smad signaling in hepatic fibrosis.

The transforming growth factor-β (TGF-β)/Suppressor of Mothers against Decapentaplegic (Smad) signaling pathway plays an important role in the pathogenesis and progression of liver fibrosis. This current study was conducted to investigate the effect of semaglutide (SEMA), a glucagon-like peptide-1 (GLP-1) receptor agonist, in a mouse model of liver fibrosis. The mice received thioacetamide (TAA) (150 mg/kg, biweekly) via intraperitoneal (i.p.) injection for nine consecutive weeks to induce liver fibrosis. SEMA was administered orally once daily at a dose of 0.12 mg/kg. Administration of SEMA improved liver function as demonstrated by the reduction in the plasma levels of aminotransferases and gamma-glutamyl transpeptidase (GGT) along with the rise in serum albumin level. Moreover, SEMA mitigated the TAA-induced histopathological changes and reduced the content of α-smooth muscle actin (α-SMA). SEMA ameliorated the TAA-induced oxidative stress by mitigating the derangement in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, reducing glutathione (GSH) levels, and decreasing malondialdehyde (MDA) levels. The hepatic TGF-β/Smad signaling pathway was downregulated by SEMA treatment, while sirtuin 1 (SIRT1) content and phosphorylated AMP-activated protein kinase (p-AMPK) expression were upregulated. SEMA significantly reduced the severity of liver fibrosis induced by TAA through SIRT1 activation. And it holds promise as a therapeutic agent for liver fibrosis.