Ethanol-induced liver injury is alleviated by chrysin via increasing MRP2 transporter expression and enhancing the Nrf2-mediated adaptive response.

Alcoholic liver disease (ALD), a major cause of alcohol-related mortality, encompasses a spectrum of liver damage that progress through steatosis, alcoholic steatohepatitis (ASH), fibrosis/cirrhosis, and ultimately hepatocellular carcinoma (HCC). Although chrysin exhibits hepatoprotective effects, its molecular mechanisms in ALD remain incompletely understood. Here, we integrated bioinformatics and experimental validation to demonstrate that chrysin, a flavonoid with hepatoprotective properties, directly targets the microsomal ethanol-oxidizing system (MEOS) to suppress its activity, thereby reducing ethanol-induced oxidative stress (OS) and liver injury. Additionally, chrysin upregulated alcohol-metabolizing enzymes (ADH/ALDH), further decreasing reactive oxygen species (ROS) generation. In an ASH rat model, chrysin ameliorated liver histopathology, reduced serum transaminases, and attenuated mitochondrial apoptosis. Mechanistically, it activated the Nrf2/MRP2 antioxidant pathway and mitigated endoplasmic reticulum stress (ERS) via inhibition of the PERK-ATF4-CHOP axis. Collectively, these findings identify chrysin as a promising therapeutic candidate for Alcohol-related liver injury by modulating ethanol metabolism, alleviating oxidative damage, and protecting against ER stress.