Background: Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyper proliferation. Ginsenoside compound K (CK), a bioactive metabolite of ginseng, modulates various skin disorders with an impact on keratinocyte biology. However, the effect of Ginsenoside CK in psoriasis has not been explored. Objective: Our aim was to investigate whether ginsenoside CK could affect the homeostasis of keratinocytes and their expression of psoriasis-associated antimicrobial protein regenerating islet-derived protein 3-alpha (REG3A) and its murine ortholog RegIII gamma. We further explored the therapeutic potential of ginsenoside CK in imiquimod (IMQ)-induced psoriasis-like dermatitis. Methods: The effects of ginsenoside CK in cell growth and apoptosis of human keratinocytes were measured by MTT assay and flow cytometry, respectively. Bax levels were evaluated by Western blot in HaCaT cells following ginsenoside CK stimulation. REG3A levels were assessed by RT-PCR and Western blot in human keratinocytes following interleukin (IL)-36 gamma and ginsenoside CK co-simulation. Utilizing IMQ-induced psoriasis mouse model, the therapeutic effects of 0.1% and 1% ginsenoside CK cream were assessed by skin thicknesses and histological examinations, and RegIII gamma level in the lesional skin was detected by Western blot and immunofluorescence. Results: Ginsenoside CK prohibited human keratinocyte proliferation but did not affect their apoptosis. Moreover, it inhibited 1L-36 gamma-induced REG3A expression in HaCaT cells. Ginsenoside CK alleviated imiquimod-induced psoriasis-like hyperkeratosis and reduced RegIII gamma expression in the keratinocytes from lesional skin. Conclusion: Ginsenoside CK ameliorated IMQ-induced psoriasis-like dermatitis possibly through inhibiting REG3A/RegIII gamma expression in keratinocytes, which highlighted a therapeutic potential of ginsenoside CK in psoriasis. (C) 2019 Elsevier Inc. All rights reserved.