AbstractIntroductionA recent study confirmed that thiolutin (THL), as a potent inflammasome inhibitor, plays a promising therapeutic role in multiple inflammatory disease models. However, the effect of THL on psoriasis has not been reported so far.MethodsA psoriasiform dermatitis model was prepared by applying 5% imiquimod (IMQ) cream on mice. A total of 36 mice were randomly divided into six groups: control, model, model + THL‐L/M/H (THL, 1/2.5/5 mg/kg/day), model + methotrexate (1 mg/kg/day). Psoriasis area and severity index (PASI) scores were observed and calculated. The histological changes in skin, liver, and kidney tissues were observed by hematoxylin and eosin staining. Alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, and blood creatinine were measured by automatic biochemistry analyzer. The size of the spleens was determined, and the proportion of Foxp3 + CD4+ regulatory T (Treg) cells in the spleens was tested by flow cytometry. The proinflammatory factors and nucleotide oligomerization domain nucleotide oligomerization domain (NOD)‐like receptor protein 3 (NLRP3) inflammasome protein levels were examined by reverse transcription‐quantitative polymerase chain reaction, enzyme‐linked immunosorbent assay, Western blotting, and immunohistochemistry, respectively.ResultsTHL administration preeminently reduced the thickness, scaling, and erythema of the skin lesions, alleviated IMQ‐induced psoriasiform lesions in mice, reduced the PASI score, and ameliorated histopathological changes in mouse skin. The spleen index was decreased by almost half and the proportion of Foxp3 + CD4+ Treg cells was increased after intervention by THL. THL intervention did not affect liver and kidney function, but decreased the expression levels of proinflammatory factors and NLRP3 inflammasome in the skin of psoriatic mice.ConclusionsTHL may alleviate IMQ‐induced psoriasis‐like manifestations in mice by inhibiting NLRP3 inflammasome.