To investigate the intervention effect of Jiedu Huayu Granules(JDHY Granules) on acute-on-chronic liver failure(ACLF) in rats from the perspective of Kupffer cell exosome microRNA(miRNA) and explore its potential mechanism of action.Methods:Seventy rats were randomly divided into a normal group(n=10)，a model group(n=30)，and a Chinese medicine group(n=30).The ACLF rat model was established by administering a combination of carbon tetrachloride(CCl4)，lipopolysaccharide(LPS)，and D-galactosamine(D-GalN).JDHY Granules were administered orally 48 hours before model induction，and the normal and model groups were given an equal amount of distilled water.After the intervention and model completion，liver tissues and blood samples were collected from the rats.Kupffer cell exosomes were extracted from the liver tissues of each group，and the relationship between JDHY Granules and Kupffer cell exosomes was explored.High-throughput miRNA microarray technology was used to detect changes in miRNA expression in Kupffer cell exosomes from each group，and the differentially expressed miRNAs between the model and Chinese medicine groups were identified.Bioinformatics analysis of miRNA from Kupffer cell exosomes was performed，and pathway inhibitors and miRNA interference techniques were used for reverse validation to identify the potential pathways through which JDHY Granules exerted its pharmacological effects.Results:In vivo studies showed that JDHY Granules significantly protected liver function in ACLF rats and alleviated liver tissue pathological damage.In vitro studies indicated that JDHY Granules increased the expression of miR-9a-5p in Kupffer cell exosomes，which reduced liver cell damage and improved liver cell survival.This effect was likely due to the inhibition of excessive activation of the hypoxia-inducible factor(HIF) signaling pathway，a result consistent with bioinformatics analysis.Conclusion:JDHY Granules protect liver damage in ACLF rats both in vivo and in vitro by upregulating miR-9a-5p expression in Kupffer cell exosomes and inhibiting excessive activation of the HIF signaling pathway.These findings suggest its potential role in the treatment of liver diseases.