# Sotagliflozin Modulation of SIRT1/Nrf2 and PI3K/AKT Signaling Pathway Ameliorates Experimental Liver Fibrosis in Rats

## TL;DR

This study shows that sotagliflozin can reduce liver fibrosis in rats by boosting antioxidants and reducing inflammation and cell death.

## Contribution

The study reveals a novel mechanism of sotagliflozin's anti-fibrotic effects via SIRT1/Nrf2 and PI3K/AKT pathways.

## Key findings

- Sotagliflozin upregulated antioxidant markers SIRT1 and Nrf2 in TAA-induced liver fibrosis.
- Treatment reduced apoptotic and fibrogenic markers, protecting against liver damage.
- The drug inhibited PI3K/AKT signaling, suppressing inflammation and apoptosis.

## Abstract

Liver fibrosis poses a major global health burden, contributing substantially to morbidity and mortality worldwide. This study aims to assess the potential novel mechanisms behind the anti‐fibrotic effects of sotagliflozin (Sota) in thioacetamide (TAA)‐induced liver fibrosis in rats.

To induce liver fibrosis in rats, 100 mg/kg of TAA was injected intraperitoneally triweekly for 6 weeks. Treated groups were orally administered sotagliflozin (10 and 20 mg/kg) for 4 weeks, concurrent with TAA injections.

Alongside the histological alterations, the elevation of liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST), lipid profiles total cholesterol (TC) and triglycerides (TAG), cytokines tumor necrosis factor‐alpha (TNF‐α) and interleukin‐6 (IL‐6), apoptotic markers (caspase‐3 and Bcl2 associated X protein [Bax] BAX), phosphatidylinositol 3‐kinase (PI3K), phosphorylated protein kinase B (p‐AKT), and the lipid peroxidation marker malondialdehyde (MDA) indicated liver dysfunction induced by TAA. Furthermore, indicators of liver fibrosis encompassed reduced levels of albumin, antioxidants; glutathione (GSH), superoxide dismutase (SOD), heme oxygenase‐1 (HO‐1), and nuclear factor erythroid 2‐related factor 2 (Nrf2), antiapoptotic protein B‐cell lymphoma‐2 (BCL2), sirtuin‐1 (SIRT1) expression, and histopathological alterations.

This study demonstrated that daily oral treatment with sotagliflozin markedly upregulated antioxidant markers such as SIRT1 and Nrf2, attenuated TNF‐α, and reduced apoptotic and fibrogenic markers, thereby protecting against TAA‐induced liver fibrosis. This may have occurred through the augmentation of SIRT1/Nrf2 expression, the inhibition of PI3K/AKT, resulting in the suppression of apoptosis and inflammation.