Kirenol, a diterpene active component from Siegesbeckia orientalis, alleviates atopic dermatitis by suppressing TYK2

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease characterized by severe pruritus, skin barrier dysfunction, and underlying immune dysregulation. Kirenol, a major active ingredient and quality control marker from Siegesbeckia orientalis L., has been shown to possess broad pharmacological properties, ranging from anti-arthritic and anti-tumor activities to therapeutic potential in cardiovascular medicine. However, its effect on atopic dermatitis has not yet been reported.

This study aims to investigate the therapeutic efficacy and underlying molecular mechanisms of Kirenol in the treatment of atopic dermatitis.

ScRNA-seq data from skin tissues of 5 AD patients and 4 healthy donors was analyzed by Seurat in R. The direct interaction between Kirenol and Tyrosine Kinase 2 (TYK2) was assessed using molecular docking and cellular thermal shift assays (CETSA). In vitro, the anti-inflammatory mechanisms of Kirenol were evaluated in RAW264.7 murine macrophages and HaCaT human immortalized keratinocytes. In vivo, an AD murine model was established via 2,4-dinitrochlorobenzene (DNCB) sensitization and challenge. The therapeutic efficacy of Kirenol was evaluated based on clinical scoring and histological analysis.

ScRNA-seq data analysis demonstrated that TYK2 expression was elevated in keratinocytes and macrophages of atopic dermatitis patients. Molecular docking and CETSA analyses confirmed that Kirenol directly binds to the TYK2 protein. In vitro experiments demonstrated that Kirenol effectively inhibits TYK2 phosphorylation in both RAW264.7 macrophages and HaCaT keratinocytes. Consequently, Kirenol suppressed the nuclear translocation of signal transducers and activators of transcription 3 (STAT3) and downregulated the expression of TYK2-mediated proinflammatory cytokines specifically IL-12 and IL-23. In vivo, topical administration of Kirenol significantly ameliorated AD symptoms in the murine model by suppressing TYK2 protein expression and STAT3 phosphorylation in skin lesions, leading to a marked reduction in inflammatory mediators. Furthermore, Kirenol also relieved the symptoms of TYK2-mediated other dermatological diseases, such as psoriasis.

Our findings discover that Kirenol from Siegesbeckia orientalis attenuates AD through the targeted inhibition of TYK2. This study identifies a novel candidate for treating AD from a traditional Chinese medical herb and provides scientific evidence supporting its application in the management of atopic dermatitis.