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Additionally, acute lung injury (ALI) resulting from sepsis is a major cause of death in intensive care units. Macrophages are essential for maintaining normal lung physiological functions and are implicated in various pulmonary diseases. An essential autophagy protein, autophagy\u2010related protein 16\u2010like 1 (ATG16L1), is crucial for the inflammatory activation of macrophages.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>ATG16L1 expression was measured in lung from mice with sepsis. ALI was induced in myeloid <jats:italic>ATG16L1\u2010<\/jats:italic>, <jats:italic>NLRP3\u2010<\/jats:italic> and <jats:italic>STING<\/jats:italic>\u2010deficient mice by intraperitoneal injection of lipopolysaccharide (LPS, 10\u00a0mg\/kg). Using immunofluorescence and flow cytometry to assess the inflammatory status of LPS\u2010treated bone marrow\u2010derived macrophages (BMDMs). A co\u2010culture system of BMDMs and MLE\u201012 cells was established in vitro.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Myeloid <jats:italic>ATG16L1<\/jats:italic>\u2010deficient mice exhibited exacerbated septic lung injury and a more intense inflammatory response following LPS treatment. Mechanistically, <jats:italic>ATG16L1<\/jats:italic>\u2010deficient macrophages exhibited impaired LC3B lipidation, damaged mitochondria and reactive oxygen species (ROS) accumulation. These abnormalities led to the activation of NOD\u2010like receptor family pyrin domain\u2010containing protein 3 (NLRP3), subsequently enhancing proinflammatory response. Overactivated <jats:italic>ATG16L1<\/jats:italic>\u2010deficient macrophages aggravated the damage to alveolar epithelial cells and enhanced the release of double\u2010stranded DNA (dsDNA), thereby promoting STING activation and subsequent NLRP3 activation in macrophages, leading to positive feedback activation of macrophage NLRP3 signalling. Scavenging mitochondrial ROS or inhibiting STING activation effectively suppresses NLRP3 activation in macrophages and alleviates ALI. Furthermore, overexpression of myeloid <jats:italic>ATG16L1<\/jats:italic> limits NLRP3 activation and reduces the severity of ALI.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings reveal a new role for ATG16L1 in regulating macrophage NLRP3 feedback activation during sepsis, suggesting it as a potential therapeutic target for treating sepsis\u2010induced ALI.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Myeloid\u2010specific ATG16L1 deficiency exacerbates sepsis\u2010induced lung injury.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p><jats:italic>ATG16L1<\/jats:italic>\u2010deficient macrophages exhibit impaired LC3B lipidation and ROS accumulation, leading to NLRP3 inflammasome activation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Uncontrolled inflammatory responses in <jats:italic>ATG16L1<\/jats:italic>\u2010deficient macrophages aggravate alveolar epithelial cell damage.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Alveolar epithelial cells release dsDNA, activating the cGAS\u2010STING\u2010NLRP3 signaling pathway, which subsequently triggers a positive feedback activation of NLRP3.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Overexpression of <jats:italic>ATG16L1<\/jats:italic> helps mitigate lung tissue inflammation, offering a novel therapeutic direction for sepsis\u2010induced lung injury.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.70289","type":"journal-article","created":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T08:16:15Z","timestamp":1744359375000},"source":"Crossref","is-referenced-by-count":16,"title":["ATG16L1 restrains macrophage NLRP3 activation and alveolar epithelial cell injury during septic lung injury"],"prefix":"10.1002","volume":"15","author":[{"given":"Yan","family":"Bai","sequence":"first","affiliation":[{"name":"Department of Anesthesiology The First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Zhan","sequence":"additional","affiliation":[{"name":"Hepatobiliary Center The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology The First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyue","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology The First Affiliated Hospital of Nanjing Medical University  Nanjing 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