BACKGROUND: Generalized pustular psoriasis (GPP) constitutes a rare, severe inflammatory disorder that differs from psoriasis vulgaris (PV). The IL-36 pathway has been identified as a key element in GPP pathogenesis. OBJECTIVE: To explore protein expression between PV and GPP, providing insights into potential mechanisms. METHODS: We performed proteomic analysis of tissue specimens from patients with PV and GPP to identify differentially expressed proteins. Comparative analysis of the proteomic data was performed and proteins with significant differences were further identified using immunofluorescence and Western blot techniques. Differential proteins were also explored by evaluating the efficacy of IL-36R inhibitors before and after GPP treatment, providing potential avenues for targeted therapeutic strategies. RESULTS: Tissue proteomic profiling showed that matrix metallopeptidase 9 (MMP9) increased significantly in the GPP as compared to PV. Immunofluorescence and Western blot analysis confirmed that MMP9 is higher expressed in GPP. And after therapy with IL-36 inhibitors showed that the level of MMP9 expression was markedly reduced. CONCLUSION: MMP9 may be involved with the pathogenesis of GPP.