An iron-deficient diet prevents alcohol- or diethylnitrosamine-induced acute hepatotoxicity in mice by inhibiting ferroptosis

The liver is easily injured by exogenous chemicals through reactive oxygen species (ROS), which lead to fer-roptosis, a ROS-dependent programmed cell death characterized by iron accumulation and lipid peroxidation. However, whether iron restriction has a positive role in chemicals-induced liver injuries is unknown. The present study investigated the effects of an iron-deficient diet on liver injuries induced by alcohol or diethylnitrosamine (DEN). Mice were fed an iron-deficient diet for four weeks, then treated with three doses of alcohol (5 g/kg, 24 h interval, gavage) to mimic mild liver injury or five doses of DEN (50 mg/kg, 24 h interval, i. p.) to mimic severe liver failure. The results showed that mice were iron-deficient after four weeks of feeding. Interestingly, as evaluated by H&E staining of liver slices, liver/body weight ratio, serum ALT and AST, iron deficiency signifi-cantly alleviated liver injuries triggered by alcohol or DEN. The activities of alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH), and the expression of CYP2E1 were increased by iron deficiency. Mech-anistically, iron deficiency prevented the decrease of glutathione peroxidase 4 (GPX4), which eliminated malondialdehyde (MDA) by utilizing glutathione (GSH). In summary, alcohol-or DEN-induced liver injuries were mitigated by the iron-deficient diet by inhibiting ferroptosis, which might be a promising measure for preventing liver injuries induced by alcohol, DEN, or other exogenous chemicals.