Psoriasis is a common chronic immune-mediated inflammatory skin disease that presents significant challenges in clinical management. Gentiopicroside (GPS), a bioactive compound derived from Gentiana scabra, has been reported to possess anti-inflammatory and immunomodulatory properties. However, its potential role in the treatment of psoriasis remains unclear. This study aimed to investigate the therapeutic effects of GPS on psoriasis-like dermatitis and elucidate its underlying mechanisms. A psoriasis-like dermatitis model was established in BALB/c mice using imiquimod (IMQ). The therapeutic efficacy of GPS was evaluated based on clinical and histopathological improvements. Flow cytometry was used to analyze immune cell populations in the spleen and peripheral blood. In vitro, the effects of GPS on bone marrow-derived dendritic cells (BMDCs) were assessed in an inflammatory model. RNA sequencing was performed to identify differentially expressed genes and key signaling pathways in BMDCs after GPS treatment. Molecular docking was employed to predict the binding affinity between GPS and potential targets, which were further validated using Western blotting and immunofluorescence. GPS treatment significantly alleviated psoriasis-like skin lesions in IMQ-induced mice, improving both clinical manifestations and histopathological alterations. GPS reduced the proportions of lymphocytes and dendritic cells and attenuated Th17-driven inflammation, thereby contributing to a more balanced immune milieu. In vitro, GPS inhibited the maturation and activation of BMDCs. Transcriptomic profiling demonstrated that GPS modulated multiple immune- and cytokine-associated pathways, particularly the NF-κB signaling pathway. Molecular docking suggested a strong binding affinity between GPS and NF-κB p65, while Western blotting and immunofluorescence confirmed that GPS suppressed phosphorylated NF-κB p65 nuclear translocation. GPS exerts anti-psoriatic effects through multimodal mechanisms, including immunomodulation and suppression of NF-κB activation. These findings provide experimental evidence and a theoretical basis for the development of GPS as a potential therapeutic agent for psoriasis.
