Artesunate is a semi-synthetic derivative of artemisinin, an active component of the medicinal plant Artemisia annua.Artesunate is a clinically effective anti-malarial drug.Allergy is an acquired hypersensitivity reaction of the immune system mediated by cross-linking of allergen-specific IgE-bound high-affinity IgE receptors, leading to immediate mast cell degranulation.Asthma is a chronic airway disorder characterized by airway obstruction, hyperresponsiveness, oxidative damage and inflammation.Artesunate prevented IgE-mediated cutaneous vascular hyperpermeability, hypothermia, elevation in plasma histamine level and tracheal tissue mast cell degranulation in mice in a dose-dependent manner.Artesunate concentration-dependently blocked IgE-mediated degranulation of RBL2H3 mast cells and human culture mast cells.Artesunate was found to inhibit IgE-induced Syk and PLC 1 pbosphorylation, production of IP3 and rise in cytosolic Ca2+ level in mast cells.Artesunate dose-dependently inhibited OVA-induced increases in total and eosinophil counts, IL-4, IL-5, IL-13 and eotaxin levels in bronchoalveolar lavage fluid.It attenuated OVA-induced lung tissue eosinophilia and airway mucus production, mRNA expression of E-selectin, IL-17, IL-33 and Muc5ac in lung tissues, and airway hyperresponsiveness to methacholine.In normal human bronchial epithelial cells, artesunate blocked epidermal growth factor-induced phosphorylation of Akt and its downstream substrates tuberin, p70S6 kinase and 4E-binding protein 1, and transactivation of NF-κB.Oxidative damage markers 8-isoprostane, 8-hydroxy-2-deoxy-guanosine and 3-nitrotyrosine levels were potently repressed by artesunate.OVA-induced increases in pro-oxidants, iNOS and NADPH oxidase (NOX 1,2, 3 and 4) were significantly abated by artesunate.Gene expressions of regnlatory subunits of NOX, p22phox and p67phox, were also reduced by artesunate.The expressions and activities of antioxidants superoxide dismutase and catalase were substantially restored with artesunate in OVA-challenged mice.Artesunate significantly enhanced nuclear levels of nuclear factor erythroid-2-related-factor 2 (Nrf2) in lung tissues from OVA-challenged mice.We report here for the first time that artesunate possesses anti-allergic activity by blocking IgE-induced mast cell degranulation, antioxidative and antiinflammatory effects in allergic airways probably via negative regulation of PI3K/Akt pathway and the downstream NF-κB activity, and via activation of Nrf2 activity.These findings provide a novel therapeutic value for artesunate in the treatment of allergic asthma capable of controlling both inflammation and oxidative damage, and other mast cell-mediated allergic disorders.