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ISL has been proven to downregulate the productions of IL\u20101\u03b2, TNF\u2010\u03b1 and IL\u20106 by macrophages. However, detailed molecular mechanisms of this modulation remain elusive. Here, ISL suppressed Syk phosphorylation and CD80, CD86, IL\u20101\u03b2, TNF\u2010\u03b1 and IL\u20106 expressions in lipopolysaccharide\u2010stimulated macrophages ex\u00a0vivo. ApoC3\u2010transgenic (ApoC3<jats:sup>TG<\/jats:sup>) mice had more activated macrophages. ISL was also able to downregulate the inflammatory activities of macrophages from ApoC3<jats:sup>TG<\/jats:sup> mice. Administration of ISL inhibited Syk activation and inflammatory activities of macrophages in ApoC3<jats:sup>TG<\/jats:sup> mice in\u00a0vivo. The treatment of ISL further alleviated MCD\u2010induced non\u2010alcoholic fatty liver disease (NAFLD) in wild\u2010type and ApoC3<jats:sup>TG<\/jats:sup> mice, accompanied by less recruitment and activation of liver macrophages. Due to the inhibition of Syk phosphorylation, ISL\u2010treated macrophages displayed less production of cytoplasmic ROS, NLRP3, cleaved\u2010GSDMD and cleaved\u2010IL\u20101\u03b2, suggesting less inflammasome activation. Finally, the molecular docking study demonstrated that ISL bound to Syk directly with the K<jats:sub>d<\/jats:sub> of 1.273\u2009\u00d7\u200910<jats:sup>\u22128<\/jats:sup>\u2009M. When the Syk expression was knocked down by its shRNA, the inhibitory effects of ISL on activated macrophages disappeared, indicating that Syk was at least one of key docking\u2010molecules of ISL. Collectively, ISL could alleviate MCD\u2010induced NAFLD in mice involved with the inhibition of macrophage inflammatory activity by the blockade of Syk\u2010induced inflammasome activation.<\/jats:p>","DOI":"10.1111\/sji.13371","type":"journal-article","created":{"date-parts":[[2024,4,27]],"date-time":"2024-04-27T04:46:27Z","timestamp":1714193187000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Isoliquiritigenin limits inflammasome activation of macrophage via docking into Syk to alleviate murine non\u2010alcoholic fatty liver disease"],"prefix":"10.1111","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4516-2930","authenticated-orcid":false,"given":"Xiangyu","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Yangzhou Key Laboratory for Precision Treatment of Refractory Bowel Diseases The Affiliated Hospital of Yangzhou University, Yangzhou University  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