Objective To investigate the mechanism of action of paeonol improving liver and brain inflammation and oxidative stress injury induced by acute alcohol stimulation in mice based on the on Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway.Methods C57BL/6 mice were randomly divided into blank group,model group, silybin group (36.8 mg/kg),and high-,middle-,and low-dose paeonol groups (480, 240, and 120 mg/kg),with 15 mice in each group.During the adaptive phase, the mice in all groups were given Lieber-DeCarli control liquid feed freely;during modeling, the mice in the blank group were given Lieber-DeCarli control liquid feed freely,and those in the other groups were given Lieber-DeCarli alcohol liquid feed freely and the corresponding drug by gavage for 10 days. The mice were measured in terms of blood lipids \[triglyceride (TG) and total cholesterol (TC)\],liver function \[alanine aminotransferase (ALT) and aspartate aminotransferase (AST)\],inflammatory factors \[interleukin-6(IL-6), interleukin-1α(IL-1α),interleukin-1β (IL-1β),and tumor necrosis factor-α (TNF-α)\],and oxidative stress indicators \[catalase (CAT),glutathione(GSH),superoxide dismutase(SOD),and malondialdehyde (MDA)\]; HE staining and oil red O staining were used to observe the pathological changes of the liver and brain;Western blot,immunofluorescence assay,and qRT-PCR were used to measure the expression levels of Keap1/Nrf2/ARE signaling pathway-related proteins and their mRNA expression levels in mouse liver and brain.Results Compared with the model group,the high-dose paeonol group had a significant increase in body weight (P<0.05),significant increases in blood lipids (TG and TC), liver function parameters (ALT and AST),inflammatory factors (IL-6,IL-1α,IL-1β,and TNF-α),and oxidative stress indicators (CAT,GSH,and SOD) (P<0.05),and a significant reduction in the content of MDA (P<0.05);there were significant increases in the protein and mRNA expression levels of heme oxygenase-1,NAD(P)H quinone oxidoreductase 1,and glutamate-cysteine ligase catalytic subunit and significant reductions in the protein and mRNA expression levels of Keap1 in mouse liver and brain (P<0.05);the high-dose paeonol group showed significant improvements in the pathological state of the mouse liver and brain.Conclusion Paeonol can significantly alleviate alcohol-induced liver and brain inflammation and oxidative stress injury in mice,possibly by regulating the Keap1/Nrf2/ARE signaling pathway.