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We identified isochlorogenic acid C (ICGAC) as a potential natural medicine for the treatment of asthma. However, the bioavailability of ICGAC was low, ranging from 14.4% to 16.9%, suggesting the involvement of the gut microbiota. The full spectrum of ICGAC\u2019s anti-asthmatic mechanism remains to be elucidated. This study investigated the mechanism by which ICGAC alleviates allergic asthma through the gut\u2013lung axis. We discovered anti-asthma pathways and targets based on the selective regulation of lipid peroxidation and employed pharmacological tools to preliminarily validate their mechanisms and efficacy. To study the role of ICGAC in regulating the gut microbiota, we performed 16S rRNA gene sequencing and metabolite analysis. Furthermore, by combining molecular biology and lipid metabolomics, we elucidated the underlying anti-asthma mechanisms of ICGAC. The effective form of ICGAC varies between single and long-term administration. The oral administration of ICGAC enhances the gut-microbiota-derived production of short-chain fatty acids (SCFAs) as the active substances, modulates immune cell activity, influences the differentiation of T- and B-cells, and reduces airway inflammation. ICGAC also regulates the metabolic network of lipid mediators (LMs) and polyunsaturated fatty acids (PUFAs), thus exerting anti-inflammatory effects by modulating arachidonate lipoxygenase (ALOX) activity and LM levels. In addition, ICGAC enhanced the antioxidant response by upregulating the expression of glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), and nuclear factor erythroid 2-related factor 2 (Nrf2), while inhibiting the release of interleukin-4 (IL-4), thereby suppressing asthma inflammation and IgE production. The anti-asthmatic mechanism of oral ICGAC involves the inhibition of lipid peroxidation by chlorogenic acid (CGA) and SCFAs produced by the gut microbiota. ICGAC suppresses asthma-associated inflammatory and oxidative stress responses through the upregulation of GPX4, SLC7A11, and Nrf2 in lung tissue. This study not only provides a solid foundation for the potential clinical use of ICGAC in asthma treatment but also offers novel insights for future research and therapeutic strategies targeting asthma.<\/jats:p>","DOI":"10.3390\/ijms26104864","type":"journal-article","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T11:54:26Z","timestamp":1747655666000},"page":"4864","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Isochlorogenic Acid C Alleviates Allergic Asthma via Interactions Between Its Bioactive Form and the Gut Microbiome"],"prefix":"10.3390","volume":"26","author":[{"given":"Jing-Yi","family":"Xu","sequence":"first","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, Ding 11 Xueyuan Road, Beijing 100083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Juan","family":"Rong","sequence":"additional","affiliation":[{"name":"Xinjiang Institute of Material Medica, Urumqi 830004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Shen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Dan","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Xuan","family":"Zhang","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, Ding 11 Xueyuan Road, Beijing 100083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Chen","family":"Ding","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, Ding 11 Xueyuan Road, Beijing 100083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Wang","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, Ding 11 Xueyuan Road, Beijing 100083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0073-4357","authenticated-orcid":false,"given":"Yan-Xing","family":"Han","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8114-7992","authenticated-orcid":false,"given":"Tian-Le","family":"Gao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, 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, Ding 11 Xueyuan Road, Beijing 100083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1186\/s12931-023-02475-6","article-title":"Global, regional, and national burden of asthma and its attributable risk factors from 1990 to 2019: A systematic analysis for the Global Burden of Disease Study 2019","volume":"24","author":"Wang","year":"2023","journal-title":"Respir. 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