BACKGROUND Eczematous eruption (EE) is an adverse effect observed in psoriasis patients undergoing interleukin (IL)-17A inhibitor therapy, with reported incidence rates ranging from 2.2% to 12.1%. In some cases, this reaction leads to discontinuation of treatment. However, the underlying mechanism of EE development remains unclear. Therefore, we aimed to elucidate the pathogenesis of EE associated with anti-IL-17A treatment and identify pathogenic molecules involved. METHODS Skin samples were collected from psoriasis patients both before and after anti-IL-17A treatment, and the treated skin included those with and without EE. Transcriptomic profiling was performed using bulk RNA-seq and scRNA-seq, which were further validated by histopathological analysis and protein assay. In addition, in vitro experiments were conducted to explore the underlying mechanisms. RESULTS Bulk RNA-seq analysis revealed significantly elevated IL-21 expression in EE lesions, along with marked enrichment of Th2/Th22 pathways and activation of JAK-STAT signaling compared to baseline and non-EE samples. Immunohistochemistry confirmed increased expression of IL-21, pJAK1, and pSTAT3 in EE lesions. ELISA and LEGENDplex assays detected higher levels of IL-21, IL-13, and IL-22, with positive correlations between IL-21 and the latter two cytokines. ScRNA-seq localized IL-21 expression predominantly to T cells within EE lesions, which co-expressed high levels of IL-13 and IL-22. In vitro, rhIL-21 stimulation activated JAK1/STAT3 signaling and increased IL-13 and IL-22 secretion, which were suppressed by JAK1 inhibition. These findings identify IL-21 as an important regulator of Th2/Th22 responses and JAK-STAT signaling in EE pathogenesis. CONCLUSIONS IL-21 is an important inflammatory mediator contributing to the development of EE.