AIM: To observe the effects and mechanisms of hederagenin (HDG) in improving psoriasis skin lesions and inflammation in mice. METHODS: A mouse model of psoriasis was established by depilation of the back and continuous application of imiquimod for 7 days in C57 mice. After modeling, HDG was administered orally (low dose: 25 mg·kg-1·d-1 and high dose: 50 mg·kg-1·d-1) 1 hour later, and a positive control group was treated with dexamethasone. After 7 days of drug intervention, pathological, immunohistochemical, immunofluorescence, ELISA, real-time quantitative PCR, and Western blot analyses were performed on the skin lesions of each group of mice. RESULTS: Compared with the model group, the HDG intervention group showed varying degrees of improvement in skin pathological damage and inflammatory cell infiltration. Real-time PCR and ELISA results of skin tissue suspension confirmed that the mRNA and protein levels of inflammatory factors IL-1β, IL-6, and TNF-α in mouse skin were reduced in the HDG intervention group compared to the model group, indicating a significant anti-inflammatory effect of HDG. Immunohistochemical and Western blot results showed that compared with the normal group, the protein expression of Mincle in the skin of the model group mice was significantly increased, which was significantly down-regulated after HDG intervention. Immunofluorescence confirmed the co-localization of Mincle expression and macrophage marker F4/80 in the skin of the model group. Western blot analysis revealed that HDG not only down-regulated the protein level of Mincle in the treatment group but also reduced the protein phosphorylation levels of downstream signaling molecules Syk and NF-κB. CONCLUSION: Hederagenin intervention can significantly inhibit pathological damage and macrophage-related inflammation in psoriasis, and its potential molecular mechanism may be related to the down-regulation of the Mincle/Syk/NF-κB signaling pathway.