Arsenic is a toxic metalloid found in the environment in different organic and inorganic forms. Molecular mechanisms implicated in arsenic hepatotoxicity are complex but include oxidative stress, apoptosis, and autophagy. The current study focused on the potential protective capacity of melatonin against arsenic‐induced hepatotoxicity. Thirty‐six male Wistar rats were allocated into control, arsenic (15 mg/kg; orally), arsenic (15 mg/kg) plus melatonin (10, 20, and 30 mg/kg; intraperitoneally), and melatonin alone (30 mg/kg) groups for 28 days. After the treatment period, the serum sample was separated to measure liver enzymes (AST and ALT). The liver tissue was removed and then histological alterations, oxidative stress markers, antioxidant capacity, the levels of Nrf2 and HO‐1, apoptosis (Bcl‐2, survivin, Mcl1, Bax, and caspase‐3), and autophagy (Sirt1, Beclin‐1, and LC3 II/I ratio) proteins, as well as the expression level of miR‐34a, were evaluated on this tissue. Arsenic exposure resulted in the enhancement of serum AST, ALT, and substantial histological damage in the liver. Increased levels of malondialdehyde, a lipid peroxidation marker, and decreased levels of physiological antioxidants including glutathione, superoxide dismutase, and catalase were indicators of arsenic‐induced oxidative damage. The levels of Nrf2, HO‐1, and antiapoptotic proteins diminished, while proapoptotic and autophagy proteins were elevated in the arsenic group concomitant with a low level of hepatic miR‐34a. The co‐treatment of melatonin and arsenic reversed the changes caused by arsenic. These findings showed that melatonin reduced the hepatic damage induced by arsenic due to its antioxidant and antiapoptotic properties as well as its regulatory effect on the miR‐34a/Sirt1/autophagy pathway.

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