Zingerone Targets LKB1/AMPK to Block FcεRI-Dependent Mast Cell Degranulation and Anaphylaxis

AMP-activated protein kinase (AMPK) acts as a cellular energy sensor and a central regulator of metabolism. Recent studies indicate that pharmacological AMPK activation can simultaneously ameliorate metabolic disorders (e.g., type II diabetes, obesity) and allergic diseases. Zingerone, a primary bioactive compound in ginger, demonstrates protective effects in vascular calcification, non-alcoholic fatty liver disease, and asthma via AMPK activation. This study aimed to evaluate the anti-allergic activity of Zingerone and elucidate its AMPK-dependent mechanisms. In vitro, Zingerone suppressed FcεRI-mediated phosphorylation of PLCγ1, Akt, ERK1/2, JNK, p38, and IKK, while reducing β-hexosaminidase release, eicosanoid (LTC₄/PGD₂) generation, pro-inflammatory cytokine (TNF-α/IL-6) secretion, and CA²⁺ influx through LKB1/AMPK activation. In vivo, Zingerone (25-50 mg/kg, oral) attenuated passive cutaneous anaphylaxis (reduced Evans blue extravasation) and systemic anaphylaxis (inhibited histamine/LTC₄/PGD₂ release). These findings demonstrate that Zingerone inhibits FcεRI-dependent mast cell activation and anaphylaxis via the LKB1/AMPK pathway, highlighting its therapeutic potential for mast cell-mediated allergic diseases.