Toxicology mechanisms and methods · 2026
Saxagliptin Attenuates Thioacetamide-Induced Liver Fibrosis in Rats in Association with Changes in SIRT1/Nrf2/HO-1 Signaling, Oxidative Stress, and Apoptosis.
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Alsugoor Mahdi H, ALSuhaymi Naif, El Awdan Sally A, Elmadani Mevidette, Moustafa Passant E, E Shabana Marwa, El-Kashef Dalia H, Fayed Hany M
Аннотация
PURPOSE: Currently, no universally effective treatment exists to stop or reverse the development of liver fibrosis. Saxagliptin (SAX), a dipeptidyl peptidase-4 (DPP-4) inhibitor, has demonstrated extra-glycemic benefits, including anti-inflammatory and anti-apoptotic properties, but its role in hepatic fibrogenesis has not been characterized. This study examined the protective potential and underlying mechanisms of saxagliptin against thioacetamide (TAA)-induced hepatic fibrogenesis in rats.
METHODS: Twenty-four male Wistar rats were randomly allocated to four groups: control, TAA-induced fibrosis, TAA + saxagliptin (5 mg/kg), and TAA + saxagliptin (10 mg/kg). Biochemical, molecular, and histopathological analyses were conducted to assess liver injury, lipid profile, oxidative stress, inflammatory and fibrotic markers, apoptosis, and key cytoprotective signaling pathways.
RESULTS: TAA induced significant liver injury, oxidative stress, inflammation, apoptosis, and fibrosis, together with suppression of SIRT1 and Nrf2/HO-1 pathways. Saxagliptin was associated with improvements in hepatotoxicity, dyslipidemia, oxidative-stress, inflammatory, apoptotic, and fibrosis-related parameters, together with increased SIRT1 and Nrf2/HO-1 protein levels. The higher dose generally produced greater numerical improvement across several endpoints. Histopathological and immunohistochemical analyses showed reduced fibrosis-related changes and α-SMA immunoreactivity, with the higher dose (10 mg/kg) associated with hepatic architecture and fibrosis scores approaching the control findings.
CONCLUSION: Saxagliptin was associated with attenuation of TAA-induced hepatic fibrosis and improvements in oxidative stress, inflammation, apoptosis, and fibrosis-related signaling. These findings are consistent with involvement of SIRT1- and Nrf2/HO-1-associated cytoprotective responses but do not establish pathway causality. Further mechanistic studies are required to determine whether these pathways are necessary for the observed effects.
METHODS: Twenty-four male Wistar rats were randomly allocated to four groups: control, TAA-induced fibrosis, TAA + saxagliptin (5 mg/kg), and TAA + saxagliptin (10 mg/kg). Biochemical, molecular, and histopathological analyses were conducted to assess liver injury, lipid profile, oxidative stress, inflammatory and fibrotic markers, apoptosis, and key cytoprotective signaling pathways.
RESULTS: TAA induced significant liver injury, oxidative stress, inflammation, apoptosis, and fibrosis, together with suppression of SIRT1 and Nrf2/HO-1 pathways. Saxagliptin was associated with improvements in hepatotoxicity, dyslipidemia, oxidative-stress, inflammatory, apoptotic, and fibrosis-related parameters, together with increased SIRT1 and Nrf2/HO-1 protein levels. The higher dose generally produced greater numerical improvement across several endpoints. Histopathological and immunohistochemical analyses showed reduced fibrosis-related changes and α-SMA immunoreactivity, with the higher dose (10 mg/kg) associated with hepatic architecture and fibrosis scores approaching the control findings.
CONCLUSION: Saxagliptin was associated with attenuation of TAA-induced hepatic fibrosis and improvements in oxidative stress, inflammation, apoptosis, and fibrosis-related signaling. These findings are consistent with involvement of SIRT1- and Nrf2/HO-1-associated cytoprotective responses but do not establish pathway causality. Further mechanistic studies are required to determine whether these pathways are necessary for the observed effects.