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Macrophage pyroptosis reportedly plays a vital role in ALI. Although it has been established that angiotensin receptor blockers (ARBs) can reduce sepsis\u2010induced organ injury, the efficacy of sacubitril\/valsartan (SV) for sepsis has been largely understudied. Here, we aimed to investigate the role of SV in sepsis\u2010induced ALI. Caecal ligation and puncture (CLP) were used to induce polymicrobial sepsis and related ALI. The therapeutic effects of SV in CLP mice were subsequently assessed. Gasdermin D (GSDMD)\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice were used to validate the signalling pathways affected by SV.\n                    <jats:italic>In\u2009vitro<\/jats:italic>\n                    , mouse bone marrow\u2010derived macrophages (BMDMs) and Raw264.7 cells were treated with SV following exposure to lipopolysaccharide and adenosine triphosphate. Finally, the serum obtained from 42 septic patients was used for biochemical analysis. Compared to the other ARBs, SV yielded more pronounced anti\u2010inflammatory effects on macrophages.\n                    <jats:italic>In\u2009vivo<\/jats:italic>\n                    , SV decreased mortality rates, significantly reduced lung damage and prevented the inflammatory response in CLP mice. In addition, SV suppressed GSDMD\u2010mediated macrophage pyroptosis in mice. In BMDMs and Raw264.7 cells, the anti\u2010inflammatory and anti\u2010pyroptosis properties of SV were verified. SV treatment effectively inhibited NLRP3 inflammasome activation and prevented macrophage pyroptosis in a GSDMD\u2010dependent manner. Furthermore, we found that septic individuals had considerably higher serum angiotensin II levels. Overall, we found that SV might prevent ALI in CLP mice by inhibiting GSDMD\u2010mediated pyroptosis of macrophages. Thus, SV might be a viable drug for sepsis\u2010induced ALI.\n                  <\/jats:p>","DOI":"10.1111\/febs.16696","type":"journal-article","created":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T01:39:39Z","timestamp":1670290779000},"page":"2180-2198","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Sacubitril\/valsartan alleviates sepsis\u2010induced acute lung injury via inhibiting\n                    <scp>GSDMD<\/scp>\n                    \u2010dependent macrophage pyroptosis in mice"],"prefix":"10.1111","volume":"290","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1680-7872","authenticated-orcid":false,"given":"Jun","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Emergency Medicine, Nanfang Hospital Southern Medical University  Guangzhou China"},{"name":"Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital Southern 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