6-shogaol suppresses MAPK14 to attenuate endoplasmic reticulum stress and alleviate alcohol-associated liver disease.

BACKGROUND

Alcohol-associated liver disease (ALD) constitutes an acute and life-threatening condition, which may lead to the failure of multiple organs. Its characteristics are complex pathophysiological processes and high mortality rate. 6-shogaol, a bioactive ginger-derived compound, exhibits immunomodulatory, anti-inflammatory, and anticancer activities with favorable in vivo safety. Nonetheless, its exact mechanism underlying the therapeutic effect on ALD has not been fully elucidated.

PURPOSE: The therapeutic effects and mechanistic action of 6-shogaol against ALD were investigated through network pharmacology and experimental validation.

METHOD: Network pharmacology analysis was employed to identify the candidate bioactive monomer from ginger with potential therapeutic effects against ALD. An in vitro ALD model was established by treating AML-12 cells with EtOH, followed by bioactivity screening. Bioactive compounds' protective effects against ALD were systematically evaluated in cell-based assays. To investigate the underlying mechanisms, transcriptomic analysis was performed alongside molecular biology techniques, including Western blotting, immunofluorescence, and RT-qPCR.

RESULT: 10 compounds were identified from ginger through network pharmacology, with 6-shogaol exhibiting the most favorable oral bioavailability (OB) and drug-likeness (DL) profiles. 6-shogaol exerted hepatoprotective effects by attenuating inflammation and regulating lipid metabolism. Furthermore, network pharmacology and transcriptomic analysis revealed that MAPK14 may serve as a potential target for 6-shogaol in the alleviation of ALD. Subsequently, validation in ALD mice and EtOH-induced AML-12 cells suggested that 6-shogaol may suppress MAPK14, thereby attenuating endoplasmic reticulum stress (ERS) and ultimately ameliorating ALD.

CONCLUSION

6-shogaol is a potential bioactive component in ginger for ALD treatment by modulating MAPK14. It exerts therapeutic effects by regulating ERS, inflammation responses, and lipid metabolism processes, positioning it as a promising candidate for ALD management.