Alcohol-associated liver disease (ALD) encompasses a range of hepatic abnormalities, including isolated alcoholic steatosis, steatohepatitis, and cirrhosis. The flavanone-7-O-glycoside narirutin (NRT), the primary flavonoid in citrus peel, has antioxidant, anti-inflammatory, and lipid-lowering activity. We investigated the effects of NRT on liver injury induced by alcohol and explored the underlying mechanisms.

Zebrafish larvae were used to investigate the effects of NRT on acute exposure to ethanol (EtOH). Liver phenotypic, morphological, and biochemical assessments were performed to evaluate the hepatoprotective effects of NRT. Network pharmacology and molecular docking analyses were conducted to identify candidate targets of NRT in EtOH-induced liver injury. A drug affinity responsive target stability (DARTS) assay was conducted to evaluate the binding of NRT to mitogen-activated protein kinase 14 (MAPK14). The mechanism of action of NRT was validated by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) and Western blot analysis.

The liver phenotypic, morphological, and biochemical assessments revealed that NRT has potential therapeutic effects against acute EtOH-induced liver injury. RT-qPCR confirmed that NRT reversed the change in the expression of genes related to oxidative stress, lipogenesis, and the endoplasmic reticulum (ER)/unfolded protein response pathway. Network pharmacology and molecular docking analyses identified potential targets of NRT’s protective effects and confirmed that NRT regulates the p38 MAPK signaling pathway by targeting mitogen-activated protein kinase 14 (MAPK14).

NRT mitigates alcohol-induced liver injury by preventing lipid formation, protecting the antioxidant system, and suppressing ER stress–induced apoptosis through MAPK14 modulation.