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Caffeic acid (CA) and ferulic acid (FA) are both well\u2010known antioxidant and anti\u2010inflammatory phenolic acids, which resemble in chemical structure. Here we found that CA, but not FA, protects macrophages from both Nigericin\u2010induced canonical and cytosolic lipopolysaccharide (LPS)\u2010induced non\u2010canonical pyroptosis and alleviates LPS\u2010induced mice sepsis. It significantly improved the survival of pyroptotic cells and LPS\u2010challenged mice and blocked proinflammatory cytokine secretion. The anti\u2010pyroptotic effect of CA is independent of its regulations in cellular lipid peroxidation, mitochondrial function, or pyroptosis\u2010associated gene transcription. Instead, CA arrests pyroptosis by directly associating with gasdermin D (GSDMD) and blocking its processing, resulting in reduced <jats:italic>N\u2010<\/jats:italic>GSDMD pore construction and less cellular content release. In LPS\u2010induced septic mice, CA inhibits GSDMD activation in peritoneal macrophages and reduces the serum levels of interleukin\u20101\u03b2 and tumor necrosis factor\u2010\u03b1 as the known pyroptosis inhibitors, disulfiram and dimethyl fumarate. Collectively, these findings suggest that CA inhibits pyroptosis by targeting GSDMD and is a potential candidate for curbing the pyroptosis\u2010associated disease.<\/jats:p>","DOI":"10.1002\/mco2.255","type":"journal-article","created":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T06:09:31Z","timestamp":1682057371000},"source":"Crossref","is-referenced-by-count":23,"title":["Caffeic acid, but not ferulic acid, inhibits macrophage pyroptosis by directly blocking gasdermin D activation"],"prefix":"10.1002","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1249-1164","authenticated-orcid":false,"given":"Mingjiang","family":"Liu","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Basic Research With Traditional Chinese Medicine on Infectious Diseases Beijing Hospital of Traditional Chinese Medicine Capital Medical University  Beijing China"},{"name":"College of Veterinary Medicine Yangzhou University  Yangzhou China"},{"name":"Jiangsu 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