To explore the effect of Euphorbia humifusa Willd. on nonalcoholic steatohepatitis (NASH) induced by high fat diet and dextran sulfate sodium (DSS),and the molecular mechanism of its intervention.Male and female SPF grade C57BL/6 mice were randomly divided into a normal control group,a model group,and low and high dose groups of E. humifusa,10 mice in each group. The normal control group was not given any intervention,while both the model and treatment groups were fed high fat diet throughout the 14 days of the experiment,during which time the E. humifusa were orally administered by gavage daily to the mice of treatment groups.Starting from the 8th day,the model and treatment groups were given 2% DSS water for 5-7 days.Mice were executed at the end of the experiment,the serum triglyceride (TG) and alanine aminotransferase (ALT) contents were detected for all the mice.The pathological changes of mouse liver tissue were observed by H&E staining.The miRNA targeting to TLR4 was predicted based on bioinformatics and pre-experiments.The relative expressions of miR-106-5p,Toll-like receptor 4 (TLR4), IL-6 and TNF-α in the liver tissue of mice were detected by RT-qPCR.The expression levels of TLR4 and IL-1β proteins in the liver of mice were analyzed by Western blot.Compared with the normal group,the serum TG and ALT of the model group were increased. H&E staining results showed significant hepatocyte steatosis and inflammatory reaction in the model liver tissues.RT-qPCR results showed that the expressions of TLR4 and inflammatory factors (IL-6,and TNF-α) were significantly increased,while miR-106-5p which targets the TLR4,was reduced in the liver tissues of model mouse(P<0.05).Western blot results further confirmed that the expression levels of TLR4 and IL-1β proteins were increased in the liver of the model group.After the intervention with E. humifusa,the serum TG and ALT were decreased (P<0.05),the relative mRNA expression levels of TLR4 and inflammatory factors (IL-6 and TNF-α) in liver tissues were decreased,while the expression of miR-106-5p was increased compared with model group.Similarly,the expression levels of TLR4 and IL-1β proteins were decreased (P<0.05).The E. humifusa can effectively alleviates the inflammatory condition and fat deposition in NASH induced by high-fat diet combined with DSS,and its mechanism may be related to the regulation of the miR-106-5p/TLR4 signaling pathway.