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Honokiol inhibits the inflammatory response and lipid metabolism disorder by inhibiting p38α in alcoholic liver disease.

Alcoholic liver disease (ALD) is one of the leading causes of liver-related morbidity and mortality worldwide, but effective treatments are still lacking. Honokiol, a lignin-type natural compound isolated from the leaves and bark of Magnolia plants, has been widely studied for its beneficial effects on several chronic diseases. Accumulating studies have revealed that honokiol displays a potential therapeutic effect on ALD. In this study, the protective activity of honokiol on ALD was confirmed due to its significant inhibitory activity on the expression level of inflammatory cytokines (such as TNF-α, IL-6 and IL-1β) in EtOH-fed mice and in EtOH-induced AML-12 cells. Meanwhile, the expression of the lipid metabolic parameter SREBP-1c was also reduced. However, PPAR-α was increased in animal and cell experiments, which indicated that the activity of honokiol was related to its regulated activity on lipid metabolism. The findings also showed that honokiol significantly inhibited the expression level of p38α in vivo and in vitro. Blocking p38α inhibited the expression levels of TNF-α, IL-6, IL-1β and SREBP-1c but promoted the expression of PPAR-α compared with the honokiol-treated group. Moreover, forced expression of p38α further produced the opposite effect on inflammatory cytokines and lipid metabolism indicators. p38α has been related to the activation of NF-κB. In our study, honokiol significantly inhibited the phosphorylation and activation of NF-κB-pIKKα mediated by p38α. In conclusion, the results suggest that honokiol may be an effective regulator of p38α by downregulating the NF-κB pathway, thereby reducing the inflammatory response and lipid metabolism disorder in ALD.