{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T03:39:24Z","timestamp":1784086764716,"version":"3.55.0"},"reference-count":33,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Scientific Research Initiation Fund Programs","award":["KYQD(ZR)XJ2400006774"],"award-info":[{"award-number":["KYQD(ZR)XJ2400006774"]}]},{"name":"Scientific Research Initiation Fund Programs","award":["KYQD(ZR)RZ2200001179"],"award-info":[{"award-number":["KYQD(ZR)RZ2200001179"]}]},{"name":"Hainan Provincial Natural Science Foundation of China","award":["325MS023"],"award-info":[{"award-number":["325MS023"]}]},{"name":"Excellent Talent Team Project in Hainan Province","award":["HNYT20250004"],"award-info":[{"award-number":["HNYT20250004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>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 Fc\u03b5RI-mediated phosphorylation of PLC\u03b31, Akt, ERK1\/2, JNK, p38, and IKK, while reducing \u03b2-hexosaminidase release, eicosanoid (LTC4\/PGD2) generation, pro-inflammatory cytokine (TNF-\u03b1\/IL-6) secretion, and Ca2+ influx through LKB1\/AMPK activation. In vivo, Zingerone (25\u201350 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 Fc\u03b5RI-dependent mast cell activation and anaphylaxis via the LKB1\/AMPK pathway, highlighting its therapeutic potential for mast cell-mediated allergic diseases.<\/jats:p>","DOI":"10.3390\/cimb47110963","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T15:03:15Z","timestamp":1763564595000},"page":"963","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Zingerone Targets LKB1\/AMPK to Block Fc\u03b5RI-Dependent Mast Cell Degranulation and Anaphylaxis"],"prefix":"10.3390","volume":"47","author":[{"given":"Defeng","family":"Zheng","sequence":"first","affiliation":[{"name":"Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can","family":"Mao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinqiang","family":"Liang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0308-6196","authenticated-orcid":false,"given":"Xian","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.anai.2023.09.015","article-title":"Anaphylaxis: A 2023 practice parameter update","volume":"132","author":"Golden","year":"2024","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/s12016-022-08955-9","article-title":"New Mechanistic Advances in Fc\u03b5RI-Mast Cell-Mediated Allergic Signaling","volume":"63","author":"Li","year":"2022","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Yang, B.G., Kim, A.R., Lee, D., An, S.B., Shim, Y.A., and Jang, M.H. (2023). Degranulation of Mast Cells as a Target for Drug Development. Cells, 12.","DOI":"10.3390\/cells12111506"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1007\/s00018-010-0587-0","article-title":"Biological implications of preformed mast cell mediators","volume":"68","author":"Lundequist","year":"2011","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e2300284120","DOI":"10.1073\/pnas.2300284120","article-title":"Mast cell-derived prostaglandin D(2) limits the subcutaneous absorption of honey bee venom in mice","volume":"120","author":"Fujiwara","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/nri1782","article-title":"Integrated signalling pathways for mast-cell activation","volume":"6","author":"Gilfillan","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.coi.2003.09.010","article-title":"Mast cell signal transduction from the high-affinity IgE receptor","volume":"15","author":"Siraganian","year":"2003","journal-title":"Curr. Opin. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1111\/imr.12340","article-title":"Structure and dynamics of IgE-receptor interactions: Fc\u03b5RI and CD23\/Fc\u03b5RII","volume":"268","author":"Sutton","year":"2015","journal-title":"Immunol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.2337\/db13-0368","article-title":"AMPK: A target for drugs and natural products with effects on both diabetes and cancer","volume":"62","author":"Hardie","year":"2013","journal-title":"Diabetes"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.canlet.2014.01.018","article-title":"The AMP-activated protein kinase (AMPK) and cancer: Many faces of a metabolic regulator","volume":"356","author":"Faubert","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.molcel.2017.05.032","article-title":"AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance","volume":"66","author":"Garcia","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1038\/s41573-019-0019-2","article-title":"AMP-activated protein kinase: The current landscape for drug development","volume":"18","author":"Steinberg","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/j.jaci.2013.02.018","article-title":"AMP-activated protein kinase negatively regulates Fc\u03b5RI-mediated mast cell signaling and anaphylaxis in mice","volume":"132","author":"Hwang","year":"2013","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/j.jaci.2014.05.001","article-title":"ERK1\/2 antagonize AMPK-dependent regulation of Fc\u03b5RI-mediated mast cell activation and anaphylaxis","volume":"134","author":"Hwang","year":"2014","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Li, X., Lee, Y.J., Jin, F., Park, Y.N., Deng, Y., Kang, Y., Yang, J.H., Chang, J.H., Kim, D.Y., and Kim, J.A. (2017). Sirt1 negatively regulates Fc\u03b5RI-mediated mast cell activation through AMPK- and PTP1B-dependent processes. Sci. Rep., 7, Erratum in Sci. Rep. 2020, 10, 3552.","DOI":"10.1038\/s41598-017-06835-3"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1111\/all.13702","article-title":"The orphan nuclear receptor NR4A1 promotes Fc\u03b5RI-stimulated mast cell activation and anaphylaxis by counteracting the inhibitory LKB1\/AMPK axis","volume":"74","author":"Jin","year":"2019","journal-title":"Allergy"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ballester, P., Cerd\u00e1, B., Arcusa, R., Marhuenda, J., Yamedjeu, K., and Zafrilla, P. (2022). Effect of Ginger on Inflammatory Diseases. Molecules, 27.","DOI":"10.3390\/molecules27217223"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Mohammed, H.M. (2022). Zingerone ameliorates non-alcoholic fatty liver disease in rats by activating AMPK. J. Food Biochem., 46.","DOI":"10.1111\/jfbc.14149"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1016\/j.jnutbio.2014.05.009","article-title":"Ginger improves cognitive function via NGF-induced ERK\/CREB activation in the hippocampus of the mouse","volume":"25","author":"Lim","year":"2014","journal-title":"J. Nutr. Biochem."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Amin, I., Hussain, I., Rehman, M.U., Mir, B.A., Ganaie, S.A., Ahmad, S.B., Mir, M.U.R., Shanaz, S., Muzamil, S., and Arafah, A. (2021). Zingerone prevents lead-induced toxicity in liver and kidney tissues by regulating the oxidative damage in Wistar rats. J. Food Biochem., 45.","DOI":"10.1111\/jfbc.13241"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1007\/s10753-020-01320-y","article-title":"Zingerone Mitigates Carrageenan-Induced Inflammation Through Antioxidant and Anti-inflammatory Activities","volume":"44","author":"Mehrzadi","year":"2021","journal-title":"Inflammation"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1248\/yakushi.128.1195","article-title":"Effects of zingerone on fat storage in ovariectomized rats","volume":"128","author":"Han","year":"2008","journal-title":"Yakugaku Zasshi"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1016\/j.bcp.2011.08.022","article-title":"Emodin, a naturally occurring anthraquinone derivative, suppresses IgE-mediated anaphylactic reaction and mast cell activation","volume":"82","author":"Lu","year":"2011","journal-title":"Biochem. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3120","DOI":"10.1039\/D0FO01583K","article-title":"The protective role of Zingerone in a murine asthma model via activation of the AMPK\/Nrf2\/HO-1 pathway","volume":"12","author":"Zhu","year":"2021","journal-title":"Food Funct."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6526","DOI":"10.1080\/10408398.2023.2170320","article-title":"A systematic review on anti-diabetic plant essential oil compounds: Dietary sources, effects, molecular mechanisms, and safety","volume":"64","author":"Gandhi","year":"2023","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1007\/s00125-017-4342-z","article-title":"The mechanisms of action of metformin","volume":"60","author":"Rena","year":"2017","journal-title":"Diabetologia"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1515\/jbcpp-2021-0308","article-title":"AICAR promotes endothelium-independent vasorelaxation by activating AMP-activated protein kinase via increased ZMP and decreased ATP\/ADP ratio in aortic smooth muscle","volume":"33","author":"Pyla","year":"2022","journal-title":"J. Basic. Clin. Physiol. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41419-018-0324-4","article-title":"Cinacalcet-mediated activation of the CaMKK\u03b2-LKB1-AMPK pathway attenuates diabetic nephropathy in db\/db mice by modulation of apoptosis and autophagy","volume":"9","author":"Lim","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7270","DOI":"10.1158\/0008-5472.CAN-08-1484","article-title":"LKB1 is necessary for Akt-mediated phosphorylation of proapoptotic proteins","volume":"68","author":"Zhong","year":"2008","journal-title":"Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Dispenza, M.C., Bochner, B.S., and MacGlashan, D.W. (2020). Targeting the Fc\u03b5RI Pathway as a Potential Strategy to Prevent Food-Induced Anaphylaxis. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.614402"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"107247","DOI":"10.1016\/j.toxicon.2023.107247","article-title":"Promising influences of zingerone against natural and chemical toxins: A comprehensive and mechanistic review","volume":"233","author":"Shamsabadi","year":"2023","journal-title":"Toxicon"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2718","DOI":"10.1016\/j.xphs.2021.01.037","article-title":"Improvement of Oral Bioavailability and Anti-Tumor Effect of Zingerone Self-Microemulsion Drug Delivery System","volume":"110","author":"Cao","year":"2021","journal-title":"J. Pharm. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"156170","DOI":"10.1016\/j.phymed.2024.156170","article-title":"Kaixinsan regulates neuronal mitochondrial homeostasis to improve the cognitive function of Alzheimer\u2019s disease by activating CaMKK\u03b2-AMPK-PGC-1\u03b1 signaling axis","volume":"135","author":"Ren","year":"2024","journal-title":"Phytomedicine"}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/11\/963\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T15:38:30Z","timestamp":1763566710000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/11\/963"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,19]]},"references-count":33,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["cimb47110963"],"URL":"https:\/\/doi.org\/10.3390\/cimb47110963","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,19]]}}}