Nimbolide Targeting <scp>SIRT1</scp> Protects Against Acetaminophen‐Induced Acute Liver Injury by Regulating Oxidative Stress and Endoplasmic Reticulum Stress

Acetaminophen (APAP) is a major cause of acute liver injury (ALI), and N-acetylcysteine is the only approved detoxification drug. Nimbolide (Nim), which is isolated from the neem tree (Azadirachta indica), possesses protective properties against multiple diseases, including pancreatitis, autoimmune hepatitis, arthritis, and diabetic cardiomyopathy. Here, we investigated the protective effect of nimbolide on APAP-induced ALI. Male C57BL/6J mice were used to establish an ALI model via APAP administration (500 mg/kg, i.p.). All the mice received nimbolide (20 mg/kg, i.p.) or a vehicle 2 h before APAP injection. Blood and liver samples were collected at the indicated times. As expected, Nim treatment alleviated APAP-induced liver injury and inflammation in the mice. Moreover, Nim inhibited APAP-induced apoptosis by regulating endoplasmic reticulum (ER) stress. We further revealed that Nim improved mitochondrial function and increased Sirtuin 1 (SIRT1) expression. However, the protective effects of Nim were partially blocked by SIRT1 knockdown via siRNA in vitro. Our study revealed that nimbolide alleviated APAP-induced ALI by inhibiting oxidative stress and ER stress via SIRT1 activation.