{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T20:49:41Z","timestamp":1792529381026,"version":"4.5.0"},"reference-count":49,"publisher":"American Society for Clinical Investigation","issue":"24","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R35GM118337,R01GM129633,"],"award-info":[{"award-number":["R35GM118337,R01GM129633,"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01HL076179"],"award-info":[{"award-number":["R01HL076179"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,15]]},"abstract":"<jats:p>\n                    Neutrophils play a critical role in sepsis-induced acute lung injury (ALI). Extracellular cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern, promotes neutrophil heterogeneity. While delta-like ligand 4 (DLL4) expression has been studied in various cell populations, its expression in neutrophils and impact on inflammation remain unknown. Here, we discovered that eCIRP induces DLL4\n                    <jats:sup>+<\/jats:sup>\n                    neutrophils. These neutrophils trigger PANoptosis, a novel proinflammatory form of cell death initiated by Z-DNA\u2013binding protein-1 (ZBP1) in pulmonary vascular endothelial cells (PVECs). In sepsis, DLL4\n                    <jats:sup>+<\/jats:sup>\n                    neutrophils increase in the blood and lungs, upregulating ZBP1, cleaved gasdermin D, cleaved caspase-3, and phosphorylated MLKL, all of which are markers of PANoptosis, exacerbating ALI. DLL4 binds to Notch1 on PVECs and activates Notch1 intracellular domain to increase ZBP1-mediated endothelial PANoptosis. We discovered what we believe to be a novel Notch1-DLL4 inhibitor (NDI), derived from Notch1 to specifically block this interaction. Our findings reveal that NDI reduced endothelial PANoptosis in vitro and in vivo, attenuated pulmonary injury induced by DLL4\n                    <jats:sup>+<\/jats:sup>\n                    neutrophils, and decreased lung water content and permeability, indicating improved barrier function. NDI also reduced serum injury and inflammatory markers and improved survival rate in sepsis. These findings underscore the Notch1-DLL4 pathway\u2019s critical role in DLL4\n                    <jats:sup>+<\/jats:sup>\n                    neutrophil\u2013mediated ALI. Targeting the Notch1-DLL4 interaction with an NDI represents a promising therapeutic strategy for sepsis-induced ALI.\n                  <\/jats:p>","DOI":"10.1172\/jci194310","type":"journal-article","created":{"date-parts":[[2025,12,14]],"date-time":"2025-12-14T19:00:54Z","timestamp":1765738854000},"source":"Crossref","is-referenced-by-count":11,"title":["DLL4+ neutrophils promote Notch1-mediated endothelial PANoptosis to exacerbate acute lung injury in sepsis"],"prefix":"10.1172","volume":"135","author":[{"given":"Hui","family":"Jin","sequence":"first","affiliation":[{"name":"Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saoirse","family":"Holland","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alok","family":"Jha","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaifeng","family":"Ma","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingsong","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Murao","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8195-4505","authenticated-orcid":true,"given":"Monowar","family":"Aziz","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, New York, USA."},{"name":"Departments of Surgery and Molecular Medicine, Zucker School of Medicine, Manhasset, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1557-0394","authenticated-orcid":true,"given":"Ping","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, New York, USA."},{"name":"Departments of Surgery and Molecular Medicine, Zucker School of Medicine, Manhasset, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2025,12,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.0287"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/jp.2017.115"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nri2402"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00439-6"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1608077"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20220011"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-017-2752-3"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.981784"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02536"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.3MIR1118-443R"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3368"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0137721"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.30833"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1126\/science.1217726"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.791648"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2101004"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.00238"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/imr.13279"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2020.07.012"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12909"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.11.025"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.454850"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2013.1501"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-64375-z"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2016.408"},{"key":"B26","doi-asserted-by":"crossref","unstructured":"Wang S, et al. 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