Glycyrrhizin, a triterpene glycoside isolated from licorice root, has been known to exhibit anti-inflammatory activities.However, the effect of glycyrrhizin on mastitis has not been reported.The purpose of this study was to investigate the anti-inflammatory effect and mechanism of glycyrrhizin on LPS-induced mastitis in mouse.An LPS-induced mouse mastitis model was used to confirm the anti-inflammatory activity of glycyrrhizin in vivo.The primary mouse mammary epithelial cells were used to investigate the molecular mechanism and targets of glycyrrhizin.In vivo, glycyrrhizin significantly attenuated mammary gland histopathologic changes,myeloperoxidase (MPO) activity, and the infiltration of neutrophilic granulocytes;down-regulated the expression of TNF-α, IL-1β and IL-6;caused by LPS.In vitro, glycyrrhizin dose-dependently inhibited LPS-induced the expression of TNF-α, IL-6, and RANTES.Western blot analysis showed that glycyrrhizin suppressed LPS-induced NF-κB and IRF3 activation.However, glycyrrhizin did not inhibit NF-κB and IRF3 activation induced by MyD88-dependent (MyD88, IKKβ) or TRIF-dependent (TRIF, TBK1) downstream signaling components.Moreover, glycyrrhizin did not act though affecting the function of CD14 or expression of TLR4.Finally, we showed that glycyrrhizin decreased the levels of cholesterol of lipid rafts and inhibited translocation of TLR4 to lipid rafts.Moreover, glycyrrhizin activated ABCA1, which could induce cholesterol efflux from lipid rafts.In conclusion, we find that the anti-inflammatory effects of glycyrrhizin may be due to its ability to activate ABCA1.Glycyrrhizin might be a useful therapeutic reagent for mastitis and other inflammatory diseases treatment.