Saxagliptin Attenuates Thioacetamide-Induced Liver Fibrosis in Rats in Association with Changes in SIRT1/Nrf2/HO-1 Signaling, Oxidative Stress, and Apoptosis.

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.