Esculetin mitigates mast cell-mediated allergic inflammation and anaphylaxis by suppression FcεRI signaling

Mast cells are critical mediators in the initiation and propagation of allergic inflammation by secreting histamine and pro-inflammatory cytokines. Current treatments, including corticosteroids and antihistamines, provide symptomatic relief but do not directly target FcεRI-mediated mast cell activation. Esculetin, a natural bioactive compound from Fraxinus rhynchophylla Hance with potent antioxidative and anti-inflammatory effects, offers a promising but underexplored strategy for modulating allergic responses. This study investigates the pharmacological potential of esculetin in suppressing mast cell–mediated allergic inflammation. Esculetin was orally administered in immunoglobulin (Ig)E-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin-induced active systemic anaphylaxis (ASA) mouse models. PCA and ASA responses were assessed by dye extravasation, ear swelling, hypothermia, and serum levels of IgE, IL-4, and histamine. In vitro studies using RBL-2H3 cells and bone marrow–derived mast cells examined FcεRI signaling and degranulation. Esculetin administered orally led to a dose-dependent inhibition of PCA responses, reflected by decreased Evans blue dye extravasation, reduced ear tissue swelling, and suppressed mast cell degranulation. In the ASA model, esculetin markedly alleviated hypothermia and significantly reduced serum levels of IgE, interleukin (IL)-4, and histamine. In vitro analyses using RBL-2H3 cells and murine bone marrow–derived mast cells showed that esculetin suppressed degranulation by attenuating FcεRI signaling cascades. Specifically, esculetin targeted Src family kinases such as Lyn and Fyn, as well as the downstream kinase Syk, ultimately reducing intracellular calcium influx. These findings suggest that esculetin may serve as a promising therapeutic candidate for mast cell-mediated allergic inflammatory disorders by inhibiting FcεRI signaling, thereby suppressing mast cell activation.