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Myeloid differentiation protein\u20102 (MD2) has emerged as a promising therapeutic target for ALI. Herein, we aimed to evaluate the ability of isoliquiritigenin (ISL), a natural flavonoid found in licorice as a novel MD2 inhibitor, to inhibit lipopolysaccharide (LPS)\u2010induced ALI. We established a mouse ALI model and a RAW 264.7 cell injury model through LPS administration. Then, lung injury was assessed through histopathological examination, and the effects of ISL were evaluated using immunofluorescence, western blotting, reverse transcription\u2013quantitative polymerase chain reaction, flow cytometry, and enzyme\u2010linked immunosorbent assays. In addition, the interaction between ISL and MD2 was investigated through co\u2010immunoprecipitation and LPS displacement assays. Molecular docking and liquid chromatography\/mass spectrometry analyses were employed to predict the ISL\u2010binding domain of MD2. We found that ISL covalently bound to the Cysteine 133 residue of MD2, disrupting the formation of the LPS\/MD2\/toll\u2010like receptor 4 complex, and ISL significantly suppressed proinflammatory cytokine production and reactive oxygen species generation in LPS\u2010induced RAW264.7 cells. Moreover, ISL significantly alleviated lung injury in LPS\u2010induced mice, reducing pulmonary microvascular permeability, inflammatory cell infiltration, and inflammatory cytokine expression. The underlying mechanism of ISL involved the inhibition of nuclear factor kappa B and the p38 mitogen\u2010activated protein kinase pathway. Our findings supported that MD2 is the direct target of ISL in mediating its anti\u2010inflammatory response in\u00a0vivo and in\u00a0vitro, and it holds potential as a therapeutic candidate for treating ALI and other inflammatory diseases.<\/jats:p>","DOI":"10.1002\/ptr.8411","type":"journal-article","created":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T03:07:47Z","timestamp":1734577667000},"page":"922-937","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Isoliquiritigenin Exhibits Anti\u2010Inflammatory Responses in Acute Lung Injury by Covalently Binding to the Myeloid Differentiation Protein\u20102 Domain"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0097-9645","authenticated-orcid":false,"given":"Liu","family":"Yang","sequence":"first","affiliation":[{"name":"Co\u2010Construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan and Education Ministry of P.R. China, Academy of Chinese Medical Sciences Henan University of Chinese Medicine  Zhengzhou Henan Province China"},{"name":"Henan Key Laboratory of Chinese Medicine for Respiratory Disease Henan University of Chinese Medicine  Zhengzhou Henan Province China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haoran","family":"Nie","sequence":"additional","affiliation":[{"name":"Co\u2010Construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan and Education Ministry of P.R. 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China, Academy of Chinese Medical Sciences Henan University of Chinese Medicine  Zhengzhou Henan Province China"},{"name":"Henan Key Laboratory of Chinese Medicine for Respiratory Disease Henan University of Chinese Medicine  Zhengzhou Henan Province China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuyang","family":"Liu","sequence":"additional","affiliation":[{"name":"Henan Research Center for Special Processing Technology of Chinese Medicine, School of Pharmacy Henan University of Chinese Medicine  Zhengzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bangrong","family":"Cai","sequence":"additional","affiliation":[{"name":"Henan Research Center for Special Processing Technology of Chinese Medicine, School of Pharmacy Henan University of Chinese Medicine  Zhengzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6485-2371","authenticated-orcid":false,"given":"Jiansheng","family":"Li","sequence":"additional","affiliation":[{"name":"Co\u2010Construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan and Education Ministry of P.R. China, Academy of Chinese Medical Sciences Henan University of Chinese Medicine  Zhengzhou Henan Province China"},{"name":"Henan Key Laboratory of Chinese Medicine for Respiratory Disease Henan University of Chinese Medicine  Zhengzhou Henan Province China"},{"name":"Department of Respiratory Diseases The First Affiliated Hospital of Henan University of Chinese Medicine  Zhengzhou 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