Metformin ameliorates vanadium pentoxide or gamma irradiation-stimulated hepatotoxicity in male rats via targeting endoplasmic reticulum stress-induced apoptosis.

Introduction: This work aims to validate the ameliorative influence of metformin against endoplasmic reticulum stress (ERS)-prompted apoptosis caused by vanadium pentoxide (V₂O₅) or gamma-irradiation (γ-irradiation) in hepatic tissues of male rats.

Methods: There were six groups of rats: the control, metformin (100 mg/kg body weight, i.p.), V₂O₅ (12.5 mg/kg body weight, i.p), V₂O₅ plus metformin, γ-irradiation group (acute dose 6 Gy), and γ-irradiation plus metformin; for 2 weeks. Hepatic malondialdehyde (MDA) and reduced glutathione (GSH) levels were evaluated. Additionally, the protein expression of certain endoplasmic reticulum stress-related (ERS) biomarkers; Inositol requirement enzyme 1α (IRE1α), TNF receptor-associated factor 2 (TRAF2), and Apoptosis signal-regulating kinase 1 (ASK1); were estimated in hepatic tissues. Moreover, apoptosis-associated biomarkers; Bax, Bcl-2, caspase-3 and HSP70 levels have been assessed. Furthermore, histopathological changes in hepatic tissues were observed.

Results: Metformin with V₂O₅ or γ-irradiation significantly decreased MDA, IRE1α, TRAF2, ASK1, Bax, and caspase-3 compared with V₂O₅ or γ-irradiated groups. Meanwhile, it significantly elevated GSH, Bcl-2, and HSP70 levels compared to exposure to V₂O₅ or γ-irradiation groups. Interestingly, the obtained results concur well with histological alterations.

Discussion: Our findings demonstrate the protective influence of metformin against ER stress-induced apoptosis through enhancing GSH and reduction of ERS and apoptosis suggesting that metformin may have positive impacts as a potential radiation protector beyond its glucose-lowering effect.