Sappanone A Exerted Strong Anti‐Inflammatory Effects in the Treatment of Atopic Dermatitis Through <scp>IL‐21R</scp> ‐Mediated <scp>JAK1</scp> / <scp>STAT3</scp> Pathway

As a common dermatosis, atopic dermatitis (AD) is primarily driven by type 2 inflammation. Sappanone A (SA), derived from the traditional medicinal plant Caesalpinia sappan L., has demonstrated a broad range of anti-inflammatory activities in various diseases. However, the pharmacological mechanisms underlying its efficacy remain unelucidated in AD. The objective of our research was to investigate the therapeutic efficacy and molecular mechanisms of SA in treating AD. In vitro, the anti-inflammatory effects of SA were evaluated in IL-4/IL-13/TNF-α stimulated HaCaT cells. In vivo, mice were treated with SA following the induction of AD-like symptoms with MC903 and assessed for inflammatory parameters. Furthermore, transcriptomics and network pharmacology were utilized to elucidate the therapeutic mechanisms of SA in AD. SA significantly suppressed the generation of type 2 inflammatory cytokines in HaCaT cells stimulated by IL-4/IL-13/TNF-α and alleviated MC903-induced AD-like symptoms in C57BL/6J mice. The integration of transcriptomics and network pharmacology displayed that SA regulated the type 2 inflammatory response in AD through the IL-21R-mediated JAK1/STAT3 signaling pathway. SA exerted a strong anti-inflammatory role in treating AD by inhibiting the activation of the JAK1/STAT3 signaling pathway mediated by IL-21R. This research not only supports the potential of SA as a novel agent for treating AD, but also offers methods for studying compounds derived from natural herbs in AD therapy.