Jaceosidin通过泛素介导的JAK1降解治疗特应性皮炎的机制研究

Abstract

BACKGROUND Atopic dermatitis (AD) is a prevalent inflammatory skin disease with substantial clinical burden. Jaceosidin (JAC), a trihydroxy-dimethoxy flavone primarily isolated from Artemisia genus and several other plants, possesses potent immunomodulatory and anti-inflammatory activities with therapeutic potential for inflammatory skin diseases. However, its precise anti-AD mechanism remains unclear. PURPOSE This study aimed to investigate the therapeutic efficacy of JAC against AD and elucidate its underlying mechanisms. METHODS A murine AD model was established by repeated topical calcipotriol application, followed by topical JAC treatment for 7 consecutive days. Therapeutic efficacy was evaluated by ear thickness, dermatitis severity, and histopathology. TNF-α/IFN-γ-stimulated HaCaT cells and reconstructed human epidermis (RHE) models were further used for phenotypic validation and mechanistic analyses. RNA sequencing, co-immunoprecipitation, and ubiquitination assays were performed. RESULTS JAC significantly alleviated AD-like pathological manifestations in mice by reducing ear edema, mast cell infiltration, and Th2 cytokine production, while restoring epidermal barrier protein expression. Similar therapeutic effects were observed in TNF-α/IFN-γ-stimulated HaCaT cells and RHE models. Mechanistically, transcriptomic analysis identified SOCS4 as a key upstream regulator induced by JAC. JAC promoted SOCS4-mediated ubiquitin-proteasomal degradation of JAK1, leading to suppression of JAK1/STAT1 activation. CONCLUSION This study provides the first experimental evidence supporting the anti-AD effects of JAC across multiple preclinical models. JAC mitigates AD progression by restoring epidermal barrier integrity and modulating immune dysregulation through SOCS4-mediated degradation of JAK1 and subsequent suppression of JAK1/STAT signaling. These findings position JAC as a promising therapeutic candidate for AD.