Hepatoprotective Effect of Nitrate Against Methotrexate-Induced Liver Injury by Activating Wnt/β-Catenin Signaling in Mice

Methotrexate (MTX) is an effectively used drug for certain forms of cancer and autoimmune diseases. However, its hepatotoxicity severely limits its clinical use which has no effective treatment but withdrawal. Therefore, further study is required to combat the liver injury associated with MTX. Nitrate, abundant in green vegetables, possesses diverse physiological roles including anti-inflammatory, antioxidant, and immunoregulation. This study investigated the preventive effect of nitrate on MTX-induced liver injury. The liver injury model in mice was induced by a single dose of MTX (20 mg/kg) injected intraperitoneally (i.p.). Administration of 2 mM nitrate in drinking water 5 days prior effectively mitigated MTX-elevated serum aminotransferases, attenuated hepatic pathological injury, reduced the level of hepatic apoptosis, and restored the proliferative capacity of hepatocytes. The molecular mechanism may involve the activation of the Wnt/β-catenin pathway. In this study, the hepatoprotective effect of nitrate on drug-induced liver injury (DILI) was identified for the first time, which provides a new idea for the prevention of drug-induced liver injury in clinical practice.