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Our previous work showed that \u03b1-asaronol (\u03b1-AOL), a low-toxicity natural constituent of A. tatarinowii, exerts robust antiepileptic effects through \u03b3-aminobutyric acid (GABA)ergic modulation. Given the critical role of the peripheral GABAergic system in asthma pathogenesis and inflammation regulation, the therapeutic potential of \u03b1-AOL for asthma warrants investigation. This study evaluated the efficacy, safety, and pulmonary targeting of both nebulized and oral \u03b1-AOL. Murine asthma models were established using ovalbumin (OVA) and house dust mite (HDM). Both nebulized \u03b1-AOL (5, 10, 20 mg\/kg) and oral \u03b1-AOL were administered, with \u03b1-asarone, and albuterol as references. Histological, biochemical, and functional assessments were performed to evaluate lung inflammation, mucus secretion, cytokine levels (IL-4, IL-5, IL-13, TNF-\u03b1), airway smooth muscle (ASM) relaxation, and airway hyperresponsiveness (AHR). Pharmacokinetic and safety profiles were determined via HPLC tissue distribution analysis, human ether-a\u0300-go-go related gene (hERG) assays, and monitoring of respiratory and cardiovascular function. Nebulized \u03b1-AOL dose-dependently alleviated OVA\/HDM-induced airway inflammation, characterized by reduced inflammatory cell infiltration, cytokine release, mucus hypersecretion, and AHR. It also induced concentration-dependent ASM relaxation and demonstrated dual therapeutic activity by both preventing and reversing methacholine (Mch)-induced acute bronchospasm. Nebulization provided sustained lung targeting (\u226560 min retention). \u03b1-AOL exhibited negligible hERG inhibition (IC50 &amp;gt; 100 \u03bcM), no adverse respiratory effects, and no significant impact on blood pressure. In conclusion, nebulized and oral \u03b1-AOL possesses potent anti-inflammatory and bronchodilatory activities; the nebulized formulation shows favorable lung-targeted delivery and an excellent safety profile, positioning it as a promising inhaled candidate for asthma therapy, particularly in pediatric populations.<\/jats:p>","DOI":"10.1021\/acsptsci.6c00367","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T15:32:57Z","timestamp":1784820777000},"page":"2343-2357","source":"Crossref","is-referenced-by-count":0,"title":["Lung-Targeted Delivery\nof Nebulized \u03b1-Asaronol\nAttenuates Airway Inflammation and Hyperresponsiveness in Murine Asthma\nModels"],"prefix":"10.1021","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3489-1038","authenticated-orcid":true,"given":"Yajun","family":"Bai","sequence":"first","affiliation":[{"name":"Northwest University , , ,","place":["Xi\u2019an, P. R. China, 710069"]},{"name":"Hong-taoism Research Institute of Analytical Science and Technology Ltd. , , ,","place":["Xi\u2019an, Shaanxi Province, P. R. China, 710068"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Northwest University , , ,","place":["Xi\u2019an, P. R. China, 710069"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Wang","sequence":"additional","affiliation":[{"name":"Northwest University , , ,","place":["Xi\u2019an, P. R. China, 710069"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Liu","sequence":"additional","affiliation":[{"name":"Northwest University , , ,","place":["Xi\u2019an, P. R. China, 710069"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Diao","sequence":"additional","affiliation":[{"name":"Northwest University , , ,","place":["Xi\u2019an, P. R. China, 710069"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Sun","sequence":"additional","affiliation":[{"name":"Northwest University , , ,","place":["Xi\u2019an, P. R. China, 710069"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Zhao","sequence":"additional","affiliation":[{"name":"Northwest University , , ,","place":["Xi\u2019an, P. R. China, 710069"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Northwest University , , ,","place":["Xi\u2019an, P. R. China, 710069"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujun","family":"Bai","sequence":"additional","affiliation":[{"name":"Northwest University , , ,","place":["Xi\u2019an, P. R. China, 710069"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shixiang","family":"Wang","sequence":"additional","affiliation":[{"name":"Northwest University , , ,","place":["Xi\u2019an, P. R. China, 710069"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6245-7303","authenticated-orcid":true,"given":"Pu","family":"Jia","sequence":"additional","affiliation":[{"name":"Northwest University , , ,","place":["Xi\u2019an, P. R. China, 710069"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Zhao","sequence":"additional","affiliation":[{"name":"Northwest University , , ,","place":["Xi\u2019an, P. R. China, 710069"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Zheng","sequence":"additional","affiliation":[{"name":"Northwest University , , ,","place":["Xi\u2019an, P. R. China, 710069"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"issue":"1","key":"2026081411073528600_cit1","doi-asserted-by":"publisher","first-page":"4S","DOI":"10.1378\/chest.130.1_suppl.4S","article-title":"The global\nburden of asthma","volume":"130","author":"Braman","year":"2006","journal-title":"Chest"},{"issue":"2","key":"2026081411073528600_cit2","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/j.immuni.2020.01.007","article-title":"The role of lung\nand gut microbiota in the pathology of asthma","volume":"52","author":"Barcik","year":"2020","journal-title":"Immunity"},{"issue":"1","key":"2026081411073528600_cit3","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1111\/imr.12560","article-title":"Epigenetic\nregulation of T-helper cell differentiation,\nmemory, and plasticity in allergic asthma","volume":"278","author":"Tumes","year":"2017","journal-title":"Immunol.\nRev."},{"key":"2026081411073528600_cit4","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1007\/978-1-4614-8603-9_1","article-title":"Introduction to\nAsthma and Phenotyping","volume":"795","author":"Pillai","year":"2014","journal-title":"Adv. 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(Sweet flag) and other\nAcorus species","volume":"21","author":"Rajput","year":"2014","journal-title":"Phytomedicine"},{"key":"2026081411073528600_cit18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fphar.2014.00040","article-title":"Identification\nof both GABAA receptors and voltageactivated Na+ channels as molecular\ntargets of anticonvulsant \u03b1-asarone","volume":"5","author":"Wang","year":"2014","journal-title":"Front.\nPharmacol."},{"issue":"4","key":"2026081411073528600_cit19","first-page":"243","article-title":"Literature Review and Cause Analysis\nof Adverse Reactions Caused\nby Asarone Injection","volume":"7","author":"Wei-cong","year":"2010","journal-title":"Chinese J. 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Rep."},{"key":"2026081411073528600_cit23","doi-asserted-by":"publisher","first-page":"107760","DOI":"10.1016\/j.neuropharm.2019.107760","article-title":"Involvement of peroxisome\nproliferator-activated receptor in anticonvulsant activity of asaronol\nagainst pentylenetetrazole-induced seizures in zebrafish","volume":"162","author":"Jin","year":"2020","journal-title":"Neuropharmacology"},{"key":"2026081411073528600_cit24","doi-asserted-by":"publisher","first-page":"110727","DOI":"10.1016\/j.neuropharm.2025.110727","article-title":"\u03b1-Asaronol,\na low-toxicity \u03b1-asarone metabolite, suppresses seizures in\nzebrafish Dravet syndrome via positive modulation of GABAA receptors\nand LDH inhibition","volume":"283","author":"Sun","year":"2026","journal-title":"Neuropharmacology"},{"issue":"7","key":"2026081411073528600_cit25","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1038\/nm1604","article-title":"A GABAergic\nsystem in airway epithelium is essential for mucus overproduction\nin asthma","volume":"13","author":"Xiang","year":"2007","journal-title":"Nat. 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Pharmaceutics"},{"issue":"6","key":"2026081411073528600_cit28","doi-asserted-by":"publisher","first-page":"2088","DOI":"10.1021\/acs.molpharmaceut.7b00183","article-title":"Alleviation of Multiple\nAsthmatic\nPathologic Features with Orally Available and Subtype Selective GABAA\nReceptor Modulators","volume":"14","author":"Forkuo","year":"2017","journal-title":"Mol. Pharmaceutics"},{"issue":"1","key":"2026081411073528600_cit29","doi-asserted-by":"publisher","first-page":"L248","DOI":"10.1152\/ajplung.00131.2011","article-title":"Sr. Targeting the restricted \u03b1-subunit\nrepertoire of airway smooth muscle GABAA receptors augments airway\nsmooth muscle relaxation","volume":"302","author":"Gallos","year":"2012","journal-title":"Am. J. Physiol."},{"key":"2026081411073528600_cit30","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1016\/j.ejmech.2016.11.045","article-title":"Optimization of substituted imidazobenzodiazepines\nas novel asthma treatments","volume":"126","author":"Jahan","year":"2017","journal-title":"Eur. J. Med. Chem."},{"issue":"9","key":"2026081411073528600_cit31","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.4187\/respcare.05501139","article-title":"History\nof aerosol therapy: liquid nebulization to MDIs to DPIs","volume":"50","author":"Anderson","year":"2005","journal-title":"Respir. Care"},{"issue":"4","key":"2026081411073528600_cit32","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1016\/S0022-3476(95)70368-3","article-title":"Efficacy of\nfrequent nebulized ipratropium bromide added to frequent high-dose\nalbuterol therapy in severe childhood asthma","volume":"126","author":"Schuh","year":"1995","journal-title":"J. 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World Health Organ."},{"issue":"2","key":"2026081411073528600_cit36","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1016\/j.imbio.2014.09.016","article-title":"Mode of dendritic cell activation:\nThe decisive hand in Th2\/Th17 cell differentiation. Implications in\nasthma severity?","volume":"220","author":"Vroman","year":"2015","journal-title":"Immunobiology"},{"issue":"1","key":"2026081411073528600_cit37","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1111\/imr.12549","article-title":"Modeling TH2\nresponses and airway\ninflammation to understand fundamental mechanisms regulating the pathogenesis\nof asthma","volume":"278","author":"Foster","year":"2017","journal-title":"Immunol. Rev."},{"issue":"1","key":"2026081411073528600_cit38","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1248\/bpb.b19-00095","article-title":"Steroid-resistant\nasthma and neutrophils","volume":"43","author":"Nabe","year":"2020","journal-title":"Biol. Pharm. 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Physiol."},{"issue":"6","key":"2026081411073528600_cit41","doi-asserted-by":"publisher","first-page":"L1040","DOI":"10.1152\/ajplung.90330.2008","article-title":"Activation\nof endogenous GABAA channels\non airway smooth muscle potentiates isoproterenol-mediated relaxation","volume":"295","author":"Gallos","year":"2008","journal-title":"Am. J. Physiol."},{"issue":"10","key":"2026081411073528600_cit42","doi-asserted-by":"publisher","first-page":"1184","DOI":"10.1111\/cea.13713","article-title":"A new house\ndust mite-driven and mast cell-activated model of asthma in the guinea\npig","volume":"50","author":"Ramos-Ramirez","year":"2020","journal-title":"Clin. Exp. 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Pharmacol."},{"key":"2026081411073528600_cit48","unstructured":"Streamlining analysis of ion channel in\nvitro assays data to support\nclinical cardiac safety decision-making, 2024. https:\/\/www.fda.gov\/drugs\/regulatory-science-action\/streamlining-analysis-ion-channel-in-vitro-assays-data-support-clinical-cardiac-safety-decision-making."},{"key":"2026081411073528600_cit49","doi-asserted-by":"publisher","first-page":"111650","DOI":"10.1016\/j.ejmech.2019.111650","article-title":"Polygala tenuifolia-Acori\ntatarinowii herbal pair as an inspiration for substituted cinnamic\n\u03b1-asaronol esters: Design, synthesis, anticonvulsant activity,\nand inhibition of lactate dehydrogenase study","volume":"183","author":"Bai","year":"2019","journal-title":"Eur. J. Med. 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