Remogliflozin Protective Role against Experimental Liver Fibrosis by Activating AMPK/SIRT1/Nrf2 and Suppressing NF-κB Pathways

Naif ALSuhaymi¹Mahdi Alsugoor¹Aya Shokry²Hany Moawad Fayed³Bassim Mohamed³Sherif Afifi⁴Tuba Esatbeyoglu^5*Reda Korany²Marawan Elbaset³

• ¹Umm al-Qura University, Mecca, Saudi Arabia
• ²Cairo University, Giza, Giza, Egypt
• ³National Research Centre (Egypt), Cairo, Cairo, Egypt
• ⁴University of Bologna, Bologna, Emilia-Romagna, Italy
• ⁵Leibniz University Hannover, Hanover, Germany

Liver fibrosis is considered an epidemic health problem since it can lead to several insults that can be fatal. Remogliflozin (Remo), an inhibitor of the sodium-glucose cotransporter-2 (SGLT2), is one of the most recent antidiabetic drugs for type 2 diabetes mellitus (T2DM). Remo's antidiabetic and antioxidant impacts were shown in numerous animal models; however, its antifibrotic activity remains unclear. Therefore, we planned this study to clarify Remo's preventive role against thioacetamide (TAA)-induced liver fibrosis in male rats, as well as the anticipated pathways. Four groups of rats (n=6) were used in our investigation: the control group, the TAA group, received 100 mg/kg b.wt IP twice a week for six weeks, and TAA + Remo groups were given 2 doses of Remo at 25 and 50 mg/kg b.wt orally for four weeks in addition to TAA injections. TAA group showed marked elevation in liver enzymes, lipid peroxidation, and proinflammatory cytokines, as well as a marked decline in albumin and cellular antioxidant status.Additionally, the TAA group showed a marked increase in nuclear factor-κB (NF-κB) as well as a marked decrease in AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and nuclear factor erythroid 2-related factor 2 (Nrf2) levels and expressions. The harmful effects of TAA were significantly reduced by Remo therapy, which improved the aforementioned parameters.Histopathological findings corroborated biochemical results. The results of our study showed that Remo had anti-inflammatory and antioxidant properties against TAA-induced liver fibrosis by inhibiting the NF-κB pathway and activating the AMPK/SIRT1/Nrf2 pathway.