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Listeriolysin O (LLO), an indispensable virulence determinant involved in diverse pathogenic mechanisms of <jats:styled-content style=\"fixed-case\"><jats:italic>L. monocytogenes<\/jats:italic><\/jats:styled-content> infection, represents a promising therapeutic target. In this study, we sought to identify an effective inhibitor of LLO pore formation and its mechanism of action in the treatment of <jats:styled-content style=\"fixed-case\"><jats:italic>L. monocytogenes<\/jats:italic><\/jats:styled-content> infection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Haemolysis assays were carried out to screen an effective LLO inhibitor. The interaction between candidate and LLO was investigated using surface plasmon resonance and molecular docking. The effect of candidate on LLO\u2010mediated cytotoxicity, barrier disruption and immune response were investigated. Finally, the in vivo effect of candidate on mice challenged with <jats:styled-content style=\"fixed-case\"><jats:italic>L. monocytogenes<\/jats:italic><\/jats:styled-content> was examined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key results<\/jats:title><jats:p>Amentoflavone, a natural flavone present in traditional Chinese herbs, effectively inhibited LLO pore formation by engaging the residues Lys93, Asp416, Tyr469 and Lys505 in LLO. Amentoflavone dose\u2010dependently reduced <jats:styled-content style=\"fixed-case\"><jats:italic>L. monocytogenes<\/jats:italic><\/jats:styled-content>\u2010induced cell injury in an LLO\u2010dependent manner. In the Caco\u20102 monolayer model, amentoflavone maintained the integrity of the epithelial barrier exposed to LLO. Amentoflavone inhibited the inflammatory response evoked by <jats:styled-content style=\"fixed-case\"><jats:italic>L. monocytogenes<\/jats:italic><\/jats:styled-content> in an LLO\u2010dependent manner, and inhibition was attributed to ability to block perforation\u2010associated K<jats:sup>+<\/jats:sup> efflux and Ca<jats:sup>2+<\/jats:sup> influx. In the mouse infection model, amentoflavone treatment significantly reduced bacterial burden and pathological lesions in target organs, with a significant increase in survival rate.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Amentoflavone reduced the pathogenicity of <jats:styled-content style=\"fixed-case\"><jats:italic>L. monocytogenes<\/jats:italic><\/jats:styled-content> by specifically inhibiting LLO pore formation, and this may represent a potential treatment for <jats:styled-content style=\"fixed-case\"><jats:italic>L. monocytogenes<\/jats:italic><\/jats:styled-content> infection.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15827","type":"journal-article","created":{"date-parts":[[2022,3,1]],"date-time":"2022-03-01T04:10:02Z","timestamp":1646107802000},"page":"3839-3858","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Amentoflavone attenuates <scp><i>Listeria monocytogenes<\/i><\/scp> pathogenicity through an LLO\u2010dependent mechanism"],"prefix":"10.1111","volume":"179","author":[{"given":"Wang","family":"Tingting","sequence":"first","affiliation":[{"name":"State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University  Changchun China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang","family":"Tianqi","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University  Changchun China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wang","family":"Xinyu","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University  Changchun China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhang","family":"Can","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University  Changchun China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shen","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Food Science, College of Food Science and Engineering Jilin University  Changchun China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deng","family":"Xuming","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University  Changchun China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8311-0894","authenticated-orcid":false,"given":"Wang","family":"Jianfeng","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University  Changchun China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,3,28]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15542"},{"issue":"1","key":"e_1_2_12_3_1","first-page":"S1","article-title":"The concise guide to pharmacology 2021\/22: Introduction and other protein targets","volume":"178","author":"Alexander S. 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