{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T05:02:11Z","timestamp":1779858131708,"version":"3.53.1"},"reference-count":38,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T00:00:00Z","timestamp":1779667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Basic research business fund project of public welfare research institutes in Xinjiang Uygur Autonomous Region","award":["KY2024141"],"award-info":[{"award-number":["KY2024141"]}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"crossref","award":["2024ZKPYHH01"],"award-info":[{"award-number":["2024ZKPYHH01"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"crossref","award":["3332025164"],"award-info":[{"award-number":["3332025164"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the Major Consulting Project of the Chinese Academy of Engineering","award":["2025-XZ-125"],"award-info":[{"award-number":["2025-XZ-125"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Asthma is a chronic inflammatory disease with limited therapeutic options, highlighting the urgent need to explore alternative mechanisms and agents. Chlorogenic acid (CGA), a dietary polyphenol, exhibits anti-asthmatic properties, but its precise molecular mechanisms remain poorly understood. This study aimed to elucidate the mechanistic basis of CGA\u2019s anti-asthmatic effects, hypothesizing a central role in regulating polyunsaturated fatty acid metabolism and ferroptosis. An ovalbumin-induced murine asthma model was established in female BALB\/c mice to evaluate the therapeutic efficacy of CGA through inflammatory cell counts, cytokine levels (ELISA), and lung histopathology. Integrated lung lipidomics (LC-MS\/MS) was employed to profile lipid mediators and phospholipids. The underlying mechanism was investigated in erastin-induced ferroptosis in BEAS-2B cells and validated in mouse lung tissue using qPCR, immunofluorescence, and assays for reactive oxygen species (ROS) and Fe2+. CGA treatment significantly attenuated airway inflammation, reduced Th2 cytokine (IL-4, IL-5) and IgE levels, and ameliorated lung pathology in a dose-dependent manner. Lipidomics revealed that asthma was associated with dysregulated docosahexaenoic acid (DHA) metabolism, characterized by elevated pro-inflammatory lipid peroxidation products (e.g., 11-HDoHE, 14-HDoHE), a profile reversed by CGA intervention. Mechanistically, molecular docking and subsequent validation identified CGA as an activator of the Nrf2 antioxidant pathway, leading to upregulation of the key ferroptosis defense genes SLC7A11 and GPX4 both in vitro and in vivo. Consequently, CGA treatment suppressed erastin-induced ROS production and Fe2+ accumulation in BEAS-2B cells. In conclusion, this study demonstrates that CGA exerts anti-asthmatic effects by reprogramming DHA metabolism to suppress ferroptosis while enhancing antioxidant pathways. These findings reveal a novel mechanistic axis for CGA and establish that targeting lipid peroxidation-driven ferroptosis represents a promising therapeutic strategy for asthma.<\/jats:p>","DOI":"10.3390\/ijms27114747","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T14:10:22Z","timestamp":1779718222000},"page":"4747","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chlorogenic Acid Alleviates Experimental Asthma by Reprogramming DHA Metabolism to Inhibit Ferroptosis"],"prefix":"10.3390","volume":"27","author":[{"given":"Ping","family":"Zhou","sequence":"first","affiliation":[{"name":"Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gulimire","family":"Abudukeremu","sequence":"additional","affiliation":[{"name":"Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Li","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Yi","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Fine Exploration and Intelligent Development of Coal Resources, School of Chemical and Environmental Engineering, China University of Mining and Technology-Beijing, Beijing 100083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Xuan","family":"Ji","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Fine Exploration and Intelligent Development of Coal Resources, School of Chemical and Environmental Engineering, China University of Mining and Technology-Beijing, Beijing 100083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Dan","family":"Guo","sequence":"additional","affiliation":[{"name":"Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Xuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Ren","sequence":"additional","affiliation":[{"name":"Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7186-5251","authenticated-orcid":false,"given":"Lu-Lu","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Cheng","family":"Tang","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Fine Exploration and Intelligent Development of Coal Resources, School of Chemical and Environmental Engineering, China University of Mining and Technology-Beijing, Beijing 100083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayidana","family":"Wotan","sequence":"additional","affiliation":[{"name":"Xinjiang Key Laboratory for Uighur Medicine, Xinjiang Institute of Material Medica, Urumqi 830004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Juan","family":"Rong","sequence":"additional","affiliation":[{"name":"Xinjiang Key Laboratory for Uighur Medicine, Xinjiang Institute of Material Medica, Urumqi 830004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cai","family":"Tie","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Fine Exploration and Intelligent Development of Coal Resources, School of Chemical and Environmental Engineering, China University of Mining and Technology-Beijing, Beijing 100083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian-Le","family":"Gao","sequence":"additional","affiliation":[{"name":"Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Hsieh, A., Assadinia, N., and Hackett, T.L. (2023). Airway remodeling heterogeneity in asthma and its relationship to disease outcomes. Front. Physiol., 14.","DOI":"10.3389\/fphys.2023.1113100"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1002\/alr.21609","article-title":"Asthma: Definitions and pathophysiology","volume":"5","author":"Mims","year":"2015","journal-title":"Int. Forum. Allergy Rhinol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1111\/cea.13086","article-title":"New and emerging drug treatments for severe asthma","volume":"48","author":"Diver","year":"2018","journal-title":"Clin. Exp. Allergy"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"100969","DOI":"10.1016\/j.mam.2021.100969","article-title":"Corticosteroid resistance in asthma: Cellular and molecular mechanisms","volume":"85","author":"Caramori","year":"2022","journal-title":"Mol. Asp. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1186\/s13020-025-01142-w","article-title":"Naturally derived bioactive compounds as regulators of oxidative stress and inflammation in asthma","volume":"20","author":"Lee","year":"2025","journal-title":"Chin. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","article-title":"Natural products in drug discovery: Advances and opportunities","volume":"20","author":"Atanasov","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Ahmad, M., Tahir, M., Hong, Z., Zia, M.A., Rafeeq, H., Ahmad, M.S., Rehman, S.U., and Sun, J. (2024). Plant and marine-derived natural products: Sustainable pathways for future drug discovery and therapeutic development. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1497668"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Huang, J., Xie, M., He, L., Song, X., and Cao, T. (2023). Chlorogenic acid: A review on its mechanisms of anti-inflammation, disease treatment, and related delivery systems. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1218015"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Guo, Y.D., Zhang, M.X., Yu, Q.Y., Wang, L.L., Han, Y.X., Gao, T.L., Lin, Y., Tie, C., and Jiang, J.D. (2025). Hyssopus cuspidatus Boriss Volatile Extract (SXC): A Dual-Action Antioxidant and Antifungal Agent Targeting Candida albicans Pathogenicity and Vulvovaginal Candidiasis via Host Oxidative Stress Modulation and Fungal Metabolic Reprogramming. Antioxidants, 14.","DOI":"10.3390\/antiox14091046"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1016\/j.intimp.2010.07.005","article-title":"Chlorogenic acid suppresses pulmonary eosinophilia, IgE production, and Th2-type cytokine production in an ovalbumin-induced allergic asthma: Activation of STAT-6 and JNK is inhibited by chlorogenic acid","volume":"10","author":"Kim","year":"2010","journal-title":"Int. Immunopharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Nguyen, V., Taine, E.G., Meng, D., Cui, T., and Tan, W. (2024). Chlorogenic Acid: A Systematic Review on the Biological Functions, Mechanistic Actions, and Therapeutic Potentials. Nutrients, 16.","DOI":"10.3390\/nu16070924"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Aristov, V.V., Karnaukhov, A.V., Buchelnikov, A.S., Levchenko, V.F., and Nechipurenko, Y.D. (2023). The Degradation and Aging of Biological Systems as a Process of Information Loss and Entropy Increase. Entropy, 25.","DOI":"10.3390\/e25071067"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1016\/j.jaci.2013.12.1087","article-title":"Fatty acids, inflammation, and asthma","volume":"133","author":"Wendell","year":"2014","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"106477","DOI":"10.1016\/j.prostaglandins.2020.106477","article-title":"Dysregulated metabolism of polyunsaturated fatty acids in eosinophilic allergic diseases","volume":"150","author":"Miyata","year":"2020","journal-title":"Prostagland. Other Lipid Mediat."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"104341","DOI":"10.1016\/j.cellimm.2021.104341","article-title":"Lipid metabolism in asthma: Immune regulation and potential therapeutic target","volume":"364","author":"Li","year":"2021","journal-title":"Cell. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.cell.2017.09.021","article-title":"Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease","volume":"171","author":"Stockwell","year":"2017","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"17534666231208628","DOI":"10.1177\/17534666231208628","article-title":"Ferroptosis triggers airway inflammation in asthma","volume":"17","author":"Li","year":"2023","journal-title":"Ther. Adv. Respir. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"101026","DOI":"10.1016\/j.mam.2021.101026","article-title":"Molecular mechanisms of oxidative stress in asthma","volume":"85","author":"Michaeloudes","year":"2022","journal-title":"Mol. Asp. Med."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Mo, M., Chen, L., Wang, Y., Lin, X., Li, H., Chen, B., Yuan, J., and Tao, E. (2026). The gut-lung axis in childhood asthma: From early-life programming to microbiome-informed precision medicine-a narrative review. Front. Immunol., 17.","DOI":"10.3389\/fimmu.2026.1814901"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1016\/j.jaci.2025.01.031","article-title":"Sputum short-chain fatty acids, microbiome, inflammation, and mucus plugging in obstructive airway disease","volume":"155","author":"Tanabe","year":"2025","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Xu, J.Y., Rong, X.J., Shen, Z., Guo, Y.D., Zhang, Y.X., Ding, C.C., Wang, Y., Han, Y.X., Gao, T.L., and Tie, C. (2025). Isochlorogenic Acid C Alleviates Allergic Asthma via Interactions Between Its Bioactive Form and the Gut Microbiome. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26104864"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kytikova, O., Novgorodtseva, T., Denisenko, Y., Antonyuk, M., and Gvozdenko, T. (2019). Pro-Resolving Lipid Mediators in the Pathophysiology of Asthma. Medicina, 55.","DOI":"10.3390\/medicina55060284"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Rochette, L., Dogon, G., Rigal, E., Zeller, M., Cottin, Y., and Vergely, C. (2022). Lipid Peroxidation and Iron Metabolism: Two Corner Stones in the Homeostasis Control of Ferroptosis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010449"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Lee, J., and Roh, J.L. (2022). SLC7A11 as a Gateway of Metabolic Perturbation and Ferroptosis Vulnerability in Cancer. Antioxidants, 11.","DOI":"10.3390\/antiox11122444"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1007\/s00018-025-05958-5","article-title":"Ferroptosis inhibitors: Mechanisms of action and therapeutic potential","volume":"82","author":"Duo","year":"2025","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e02726","DOI":"10.1002\/advs.202502726","article-title":"EBBP-Mediated Integrated Stress Response Attenuates Anthracycline-Induced Cardiotoxicity by Inhibiting the Ferroptosis of Cardiomyocytes","volume":"12","author":"Chen","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.24976\/Discov.Med.202436186.128","article-title":"Chlorogenic Acid Alleviates High Glucose-induced HK-2 Cell Oxidative Damage through Activation of KEAP1\/NRF2\/ARE Signaling Pathway","volume":"36","author":"Dai","year":"2024","journal-title":"Discov. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1101\/gad.13.1.76","article-title":"Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain","volume":"13","author":"Itoh","year":"1999","journal-title":"Genes Dev."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Canyelles-Ni\u00f1o, M., Gonz\u00e1lez-Lafont, \u00c0., and Lluch, J.M. (2023). Hydroperoxidation of Docosahexaenoic Acid by Human ALOX12 and pigALOX15-mini-LOX. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076064"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/s00204-011-0674-5","article-title":"The cytoprotective role of the Keap1-Nrf2 pathway","volume":"85","author":"Baird","year":"2011","journal-title":"Arch. Toxicol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1042\/BJ20100415","article-title":"Thrombin-activated human platelets acutely generate oxidized docosahexaenoic-acid-containing phospholipids via 12-lipoxygenase","volume":"431","author":"Morgan","year":"2010","journal-title":"Biochem. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"27536130241231508","DOI":"10.1177\/27536130241231508","article-title":"Are Supra-Physiological Plant-Based Antioxidants Ready for the Clinic? A Scoping Review of Hormetic Influences Driving Positive Clinical Outcomes","volume":"13","author":"Wendt","year":"2024","journal-title":"Glob. Adv. Integr. Med. Health"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"106448","DOI":"10.1016\/j.isci.2023.106448","article-title":"Mitochondria hormesis delays aging and associated diseases in Caenorhabditis elegans impacting on key ferroptosis players","volume":"26","author":"Schiavi","year":"2023","journal-title":"iScience"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"112194","DOI":"10.1016\/j.cellsig.2025.112194","article-title":"KMN003 activates Nrf2 via disruption of the Keap1-Nrf2 interaction and p38-dependent transcriptional regulation","volume":"137","author":"Komeda","year":"2026","journal-title":"Cell Signal."},{"key":"ref_35","first-page":"217","article-title":"Changes in glucocorticoid receptor and phospholipase A2 in guinea pig asthma models","volume":"17","author":"Guo","year":"1994","journal-title":"Chin. J. Tuberc. Respir. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"167176","DOI":"10.1016\/j.bbadis.2024.167176","article-title":"Identifying ALOX15-initiated lipid peroxidation increases susceptibility to ferroptosis in asthma epithelial cells","volume":"1870","author":"Zhang","year":"2024","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"113187","DOI":"10.1016\/j.intimp.2024.113187","article-title":"Chicoric acid acts as an ALOX15 inhibitor to prevent ferroptosis in asthma","volume":"142","author":"Luo","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/s41420-024-01861-3","article-title":"Ferroptotic alveolar epithelial type II cells drive T(H)2 and T(H)17 mixed asthma triggered by birch pollen allergen Bet v 1","volume":"10","author":"Ma","year":"2024","journal-title":"Cell Death Discov."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/4747\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T04:10:50Z","timestamp":1779855050000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/4747"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,25]]},"references-count":38,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27114747"],"URL":"https:\/\/doi.org\/10.3390\/ijms27114747","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,25]]}}}