Vildagliptin attenuates thioacetamide-induced hepatic fibrosis in rats: associations with AMPK/SIRT1/Nrf2 and STAT3/TGF-β1 signaling.
Almikhlafi Mohannad A, Alsayb May A, Almadani Sara A, Saeedi Tahani, Alsubhi Mohammed H, Farouk Hessin Alyaa, Mahmoud Fawzy Atta Marwa, Korany Reda Ms, Fayed Hany M, El Awdan Sally A, Elbadawy Hossein M
Abstract
OBJECTIVE: Liver fibrosis is a progressive consequence of chronic injury with limited treatment options. Vildagliptin (Vilda), a dipeptidyl peptidase-4 inhibitor, possesses antioxidant and anti-inflammatory properties, but its effects on thioacetamide (TAA)-induced liver fibrosis are not fully characterized. This study evaluated Vilda in TAA-treated male rats by assessing hepatic function, oxidative stress, and signaling markers. METHODS: Rats received TAA (100 mg/kg, i.p., twice weekly for 6 weeks) alone or with Vilda (10 or 20 mg/kg, p.o., daily during weeks 3-6). Serum biochemistry, hepatic antioxidants, and specific protein concentrations (AMPK, p-AMPK, SIRT1, Nrf2, STAT3, p-STAT3, TGF-β1, and AFP) were measured. Liver sections were assessed via H&E, qualitative Masson's trichrome, and immunohistochemistry for p-AKT and SIRT1. RESULTS: TAA impaired liver function, altered lipid profiles, increased oxidative stress, and induced histopathological injury with collagen deposition. These changes coincided with altered hepatic AMPK/SIRT1/Nrf2 and STAT3/TGF-β1-associated markers, alongside PGC-1α and KEAP1 mRNA expression. Vilda treatment was associated with dose-dependent improvements in biochemical, oxidative-stress, and histopathological findings, alongside shifts in inflammation- and fibrosis-associated markers. Vilda was also associated with increased SIRT1 and reduced p-AKT immunoreactivity. CONCLUSION: Vilda treatment was associated with attenuation of TAA-induced hepatic injury and fibrotic changes in parallel with modulation of AMPK/SIRT1/Nrf2 and STAT3/TGF-β1-related markers. Because quantitative collagen morphometry and pathway-intervention experiments were not performed, these findings represent associations rather than confirmed causal mechanisms. Further studies are required to define the precise molecular interactions and translational potential of Vilda as an antifibrotic agent.
Key Findings
- Vildagliptin treatment improved liver function and reduced oxidative stress in thioacetamide-induced hepatic fibrosis in rats.
- Vildagliptin modulated key signaling pathways associated with fibrosis, including AMPK/SIRT1/Nrf2 and STAT3/TGF-β1.
- Treatment with Vildagliptin was linked to dose-dependent improvements in biochemical markers, histopathological injury, and inflammation- and fibrosis-associated markers.
Clinical Significance
These findings suggest that Vildagliptin has potential as an antifibrotic agent by attenuating oxidative stress and modulating fibrosis-related signaling pathways in liver injury, warranting further investigation for therapeutic use in hepatic fibrosis.
Citation
Almikhlafi Mohannad A, Alsayb May A, Almadani Sara Aet al.. Vildagliptin attenuates thioacetamide-induced hepatic fibrosis in rats: associations with AMPK/SIRT1/Nrf2 and STAT3/TGF-β1 signaling. Immunopharmacology and immunotoxicology. 2026-Oct-10.