Repositioning gemigliptin for the alleviation of thioacetamide-induced liver fibrosis in rats: Targeting TLR4/MAPK, SIRT1/AMPK/Nrf2, PI3K/AKT/mTOR axis and apoptosis.

There are currently few effective treatments for hepatic fibrogenesis, a prominent pathogenic characteristic of chronic liver disorders. Although dipeptidyl peptidase-4 (DPP4) inhibitors are commonly used as antidiabetic medications, which lower blood sugar levels through comparable mechanisms, each gliptin has been found to have extra protective properties. This study examined the preventive effects of the DPP4 inhibitor gemigliptin (GEM) against liver fibrosis caused by thioacetamide (TAA) and identified the underlying molecular processes. Indexes associated with hepatic fibrosis, such as biochemical parameters, histological alterations, inflammation biomarkers levels and mRNA expressions, and modifications in the expression of associated proteins in liver tissue, were evaluated. The findings demonstrated that gemigliptin therapy successfully reduced the fibrosis and liver damage brought on by TAA. Mechanistically, gemigliptin therapy reduced inflammation and oxidation stress brought on by TAA by blocking the "PI3K/AKT/mTOR and TLR4/MAPK" signaling pathways and by activating the "SIRT1/AMPK/Nrf2" pathway. By controlling the "Bcl-2/Bax/Caspase-3" pathway, we also showed that gemigliptin prevented hepatocyte apoptosis. In summary, these results imply that gemigliptin inhibits the advancement of liver fibrosis via a variety of pathways and point to the possibility of its future application in liver fibrosis treatment.