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

Sep 29, 2026

Liver fibrosis creates a major global health burden through progressive tissue remodeling that drives morbidity and mortality. In a rat model, thioacetamide (TAA) was used to induce liver fibrosis, followed by oral sotagliﬂozin treatment at 10 and 20 mg/kg. The study evaluated histology, liver injury indices (ALT, AST), lipid profiles (TC, TAG), inflammatory cytokines (TNF-α, IL-6), apoptotic markers (caspase-3, Bax/Bcl-2), and oxidative stress and pathway mediators including PI3K/p-AKT, SIRT1, and Nrf2. Sotagliﬂozin upregulated antioxidant signaling (SIRT1/Nrf2), reduced apoptosis and inflammation, and attenuated fibrosis-related changes, indicating a protective anti-fibrotic mechanism.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Introduction

Materials and Methods

Drugs and Chemicals

Experimental Animals

Results and Discussion

Conclusion and Implications

Wiley Oxidative Medicine and Cellular Longevity Volume 2025, Article ID 7684652, 14 pages [https://doi.org/10.1155/omcl/7684652](https://doi.org/10.1155/omcl/7684652) Research Article Sotagliﬂozin Modulation of SIRT1/Nrf2 and PI3K/AKT Signaling Pathway Ameliorates Experimental Liver Fibrosis in Rats Hossein M. Elbadawy, 1,2 MohannadA. Almikhlaﬁ, 1 Mohammed H. Alsubhi, 1 AyaA. Shokry,3 Hany M. Fayed ,4 Bassim M. S. A. Mohamed,4 Sherif M. Aﬁﬁ,5 Tuba Esatbeyoglu ,6 Reda M. S. Korany,7,8 and Marawan A. Elbaset 9,10 1Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University 42353, Medina, Saudi Arabia 2Health and Life Research Center, Taibah University 42353, Madinah, Saudi Arabia 3Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt 4Department of Pharmacology, National Research Centre, Medical Research and Clinical Studies Institute, 33 El-Bohouth Street, Dokki, Giza 12622, Egypt 5Department for Life Quality Studies, Rimini Campus, University of Bologna, Corso d’Augusto 237, Rimini 47921, Italy 6Department of Molecular Food Chemistry and Food Development, Institute of Food and One Health, Gottfried Wilhelm Leibniz University Hannover, Am Kleinen Felde 30 30167, Hannover, Germany 7Department of Pathology, Faculty of Veterinary Medicine, Cairo University, P. O. Box 12211, Giza, Egypt 8Department of Pathology, Faculty of Veterinary Medicine, Egyptian Chinese University, Ain Shams 4541312, Egypt 9Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA 10Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA Correspondence should be addressed to Tuba Esatbeyoglu; esatbeyoglu@foh.uni-hannover.de and Marawan A. Elbaset; [masayed@iu.edu](masayed@iu.edu) Received 6 July 2025; Revised 21 October 2025; Accepted 12 November 2025 Academic Editor: Přemysl Mladěnka Copyright © 2025 Hossein M. Elbadawy et al. Oxidative Medicine and Cellular Longevity published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Background and Purpose: 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) inthioacetamide (TAA)-induced liver ﬁbrosis in rats. Experimental Approach: To induce liver ﬁbrosis in rats, 100mg/kg of TAA was injected intraperitoneally triweekly for 6 weeks. Treated groups were orally administered sotagliﬂozin (10 and 20mg/kg) for 4 weeks, concurrent with TAA injections. Key Results: 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. Conclusion and Implications: 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 ma

FAQs

How was liver fibrosis induced and how was sotagliﬂozin administered?

Liver fibrosis was induced in rats by intraperitoneal thioacetamide (TAA) injections given triweekly for 6 weeks. Sotagliﬂozin was then administered orally at 10 or 20 mg/kg for 4 weeks concurrently with the TAA injections.

Which outcomes did the study use to assess liver injury, inflammation, and fibrosis?

The study assessed histological changes, liver enzymes (ALT and AST), lipid profiles (TC and TAG), cytokines (TNF-α and IL-6), apoptotic markers (caspase-3 and Bax/Bcl-2), and fibrosis- and oxidative-stress-related indicators including MDA and antioxidant pathways.

What mechanism did the authors propose for sotagliﬂozin’s protective effect?

The results showed increased antioxidant markers including SIRT1 and Nrf2, attenuation of TNF-α, and reduced apoptotic and fibrogenic markers. The study suggests this may involve upregulation of SIRT1/Nrf2 and inhibition of PI3K/AKT signaling, suppressing apoptosis and inflammation.

Sep 29, 2026

Upload by Indoniesian Boy