AbstractBackgroundAs a common skin disease, psoriasis is related to inflammation and immune response. Due to the frequent recurrence of psoriasis, the treatment of psoriasis remains a clinical challenge. As an effective tumor necrosis factor‐alpha (TNF‐α) inhibitor, etanercept has been used for the treatment of psoriasis. However, some patients with psoriasis have no response to etanercept or discontinue treatment. To improve the therapeutic effect of etanercept, searching the potential biomarkers and investigating the related mechanisms of etanercept in the treatment of psoriasis are vital.Materials and methodsWe stimulated HaCaT cells with lipopolysaccharide (LPS) to generate cellular psoriatic changes and established an imiquimod (IMQ)‐induced psoriasis‐like mouse model, and then used an etanercept to treat cell and mouse model.ResultsEtanercept alleviated IMQ‐induced pathological changes and inflammation, and it also decreased the protein expression of high mobility group box 1 (HMGB1), receptor for advanced glycation end‐products, and toll‐like receptor 4. Moreover, the results of in vitro experiments showed that etanercept inhibited proliferation and inflammation, and promoted cell cycle arrest and apoptosis in LPS‐treated HaCaT cells. Knockdown of HMGB1 further enhanced the inhibitory effects of etanercept on LPS‐treated HaCaT cell viability and inflammation, while overexpression of HMGB1 notably reversed the inhibitory effects of etanercept on LPS‐induced HaCaT cell viability and inflammation.ConclusionEtanercept inhibited proliferation and inflammation and promoted cell cycle arrest and apoptosis in LPS‐induced HaCaT cells, and etanercept ameliorated inflammation in a psoriasis‐like mouse model.