{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T23:06:34Z","timestamp":1789686394924,"version":"4.0.1"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":86,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Hepatic ischemia-reperfusion injury (IRI) is a serious complication during liver transplantation, which triggers a strongrepresents a significant complication in the context of liver transplantation, characterized by the induction of a robust non-specific inflammatory response throughmediated by damage-associated molecular patterns (DAMPs) and leads to, ultimately resulting in dysfunction of the transplanted liverorgan. The pathogenic pro-inflammatory (M1) polarization of hepatic macrophages is a driver of this hepatocyte injury, but the exact upstream trigger factor for this remains unclear. We investigated thecritical contributor to this hepatocellular damage; however, the precise upstream trigger remains unidentified. This study explores the potential role of neutrophil extracellular traps (NETs) as an upstream regulator of M1-type macrophage polarization. Utilizing the in vivo H-IRI mouse model alongside an in vitro macrophage co-culture system, we elucidated that the interaction between neutrophil extracellular traps (NETs) and macrophages is facilitated by the cGAS-STING signaling pathway. Our findings indicate that the double-stranded DNA generated by NETs is internalized by macrophages, subsequently activating the cytoplasmic sensor cGAS and the adaptor protein 3wSTING. This activation serves as a driver for the M1 macrophage phenotype. Our study unveils a novel and critical pathway, \u201cNETs \u2192 cGAS-STING \u2192 M1 polarization,\u201d which plays a significant role in hepatic ischemia-reperfusion injury (HIRI). This pathway presents a promising therapeutic target for mitigating graft damage following liver transplantation.<\/jats:p>","DOI":"10.1038\/s41598-026-59095-5","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T13:32:28Z","timestamp":1782307948000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neutrophil extracellular traps exacerbate liver ischemia-reperfusion injury by promoting macrophage M1 polarization via the cGAS-STING pathway"],"prefix":"10.1038","volume":"16","author":[{"given":"Dingheng","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunhai","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangxu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengli","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denghui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongjun","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"59095_CR1","doi-asserted-by":"publisher","first-page":"e030823219400","DOI":"10.2174\/1874467217666230803114856","volume":"17","author":"K Singh","year":"2024","unstructured":"Singh, K. et al. Hepatic Ischemia-reperfusion Injury: Protective Approaches and Treatment [J]. Curr. Mol. Pharmacol. 17, e030823219400 (2024).","journal-title":"Curr. Mol. Pharmacol."},{"issue":"2","key":"59095_CR2","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1002\/hep.27841","volume":"62","author":"H Huang","year":"2015","unstructured":"Huang, H. et al. Damage-associated molecular pattern-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury [J]. Hepatology 62 (2), 600\u2013614 (2015).","journal-title":"Hepatology"},{"issue":"3","key":"59095_CR3","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1038\/nm.4294","volume":"23","author":"SK Jorch","year":"2017","unstructured":"Jorch, S. K. & Kubes, P. An emerging role for neutrophil extracellular traps in noninfectious disease [J]. Nat. Med. 23 (3), 279\u2013287 (2017).","journal-title":"Nat. Med."},{"issue":"4","key":"59095_CR4","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1016\/j.ajpath.2015.11.025","volume":"186","author":"C Kawai","year":"2016","unstructured":"Kawai, C. et al. Circulating Extracellular Histones Are Clinically Relevant Mediators of Multiple Organ Injury [J]. Am. J. Pathol. 186 (4), 829\u2013843 (2016).","journal-title":"Am. J. Pathol."},{"issue":"4","key":"59095_CR5","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1038\/s41575-021-00549-8","volume":"19","author":"H Hirao","year":"2022","unstructured":"Hirao, H., Nakamura, K. & Kupiec-Weglinski, J. W. Liver ischaemia-reperfusion injury: a new understanding of the role of innate immunity [J]. Nat. Rev. Gastroenterol. Hepatol. 19 (4), 239\u2013256 (2022).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"issue":"5","key":"59095_CR6","doi-asserted-by":"publisher","first-page":"L342","DOI":"10.1152\/ajplung.00151.2012","volume":"304","author":"JM Tadie","year":"2013","unstructured":"Tadie, J. M. et al. HMGB1 promotes neutrophil extracellular trap formation through interactions with Toll-like receptor 4 [J]. Am. J. Physiol. Lung Cell. Mol. Physiol. 304 (5), L342\u2013L349 (2013).","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"issue":"7","key":"59095_CR7","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1084\/jem.20042614","volume":"201","author":"A Tsung","year":"2005","unstructured":"Tsung, A. et al. The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion [J]. J. Exp. Med. 201 (7), 1135\u20131143 (2005).","journal-title":"J. Exp. Med."},{"key":"59095_CR8","doi-asserted-by":"crossref","unstructured":"Luo, X. et al. Expression of STING Is Increased in Liver Tissues From Patients With NAFLD and Promotes Macrophage-Mediated Hepatic Inflammation and Fibrosis in Mice [J]. Gastroenterology, 155(6): (2018). 1971-84.e4.","DOI":"10.1053\/j.gastro.2018.09.010"},{"key":"59095_CR9","doi-asserted-by":"publisher","first-page":"e18761429381010","DOI":"10.2174\/0118761429381010250512060455","volume":"17","author":"Y Chen","year":"2024","unstructured":"Chen, Y. et al. Network Pharmacology and Bioinformatics of Flavonoids from Scutellaria baicalensis stems: Mitigating A\u03b2-Induced Cognitive Impairment in Rats via the MEK-ERK-CREB Pathway [J]. Curr. Mol. Pharmacol. 17, e18761429381010 (2024).","journal-title":"Curr. Mol. Pharmacol."},{"issue":"6121","key":"59095_CR10","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1126\/science.1232458","volume":"339","author":"L Sun","year":"2013","unstructured":"Sun, L. et al. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway [J]. Science 339 (6121), 786\u2013791 (2013).","journal-title":"Science"},{"issue":"2","key":"59095_CR11","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1038\/nrgastro.2012.225","volume":"10","author":"Y Zhai","year":"2013","unstructured":"Zhai, Y. et al. Ischaemia-reperfusion injury in liver transplantation\u2013from bench to bedside [J]. Nat. Rev. Gastroenterol. Hepatol. 10 (2), 79\u201389 (2013).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"59095_CR12","doi-asserted-by":"publisher","first-page":"114299","DOI":"10.1016\/j.intimp.2025.114299","volume":"150","author":"TH de Oliveira","year":"2025","unstructured":"de Oliveira, T. H., C & Gon\u00e7alves G K N. Liver ischemia reperfusion injury: Mechanisms, cellular pathways, and therapeutic approaches [J]. Int. Immunopharmacol. 150, 114299 (2025).","journal-title":"Int. Immunopharmacol."},{"issue":"10","key":"59095_CR13","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1080\/1744666X.2023.2240516","volume":"19","author":"KJ Dery","year":"2023","unstructured":"Dery, K. J. et al. New therapeutic concepts against ischemia-reperfusion injury in organ transplantation [J]. Expert Rev. Clin. Immunol. 19 (10), 1205\u20131224 (2023).","journal-title":"Expert Rev. Clin. Immunol."},{"key":"59095_CR14","doi-asserted-by":"publisher","first-page":"1054753","DOI":"10.3389\/fimmu.2022.1054753","volume":"13","author":"Y Liu","year":"2022","unstructured":"Liu, Y. et al. Neutrophil extracellular traps and complications of liver transplantation [J]. Front. Immunol. 13, 1054753 (2022).","journal-title":"Front. Immunol."},{"issue":"5","key":"59095_CR15","doi-asserted-by":"publisher","first-page":"1104","DOI":"10.7150\/ijms.52691","volume":"18","author":"H Wang","year":"2021","unstructured":"Wang, H. et al. Macrophage Polarization and Liver Ischemia-Reperfusion Injury [J]. Int. J. Med. Sci. 18 (5), 1104\u20131113 (2021).","journal-title":"Int. J. Med. Sci."},{"key":"59095_CR16","doi-asserted-by":"publisher","first-page":"1022380","DOI":"10.3389\/fimmu.2022.1022380","volume":"13","author":"F Zhang","year":"2022","unstructured":"Zhang, F. et al. The role of extracellular traps in ischemia reperfusion injury [J]. Front. Immunol. 13, 1022380 (2022).","journal-title":"Front. Immunol."},{"key":"59095_CR17","doi-asserted-by":"crossref","unstructured":"Zhao, J. et al. NETs Promote Inflammatory Injury by Activating cGAS-STING Pathway in Acute Lung Injury [J]. Int. J. Mol. Sci., 24(6). (2023).","DOI":"10.3390\/ijms24065125"},{"issue":"2","key":"59095_CR18","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1007\/s11239-023-02825-7","volume":"56","author":"APH Yokoyama","year":"2023","unstructured":"Yokoyama, A. P. H. et al. Neutrophil extracellular traps (NETs), transfusion requirements and clinical outcomes in orthotopic liver transplantation [J]. J. Thromb. Thrombolysis. 56 (2), 253\u2013263 (2023).","journal-title":"J. Thromb. Thrombolysis"},{"issue":"6","key":"59095_CR19","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1038\/s41401-023-01220-5","volume":"45","author":"XJ Li","year":"2024","unstructured":"Li, X. J. et al. The dual function of cGAS-STING signaling axis in liver diseases [J]. Acta Pharmacol. Sin. 45 (6), 1115\u20131129 (2024).","journal-title":"Acta Pharmacol. Sin"},{"key":"59095_CR20","doi-asserted-by":"crossref","unstructured":"Xiong, Y. et al. Dimethyl fumarate alleviate hepatic ischemia-reperfusion injury through suppressing cGAS-STING signaling [J]. MedComm 2025, 6(2): e70077. (2020).","DOI":"10.1002\/mco2.70077"},{"key":"59095_CR21","doi-asserted-by":"publisher","first-page":"682736","DOI":"10.3389\/fimmu.2021.682736","volume":"12","author":"D Xu","year":"2021","unstructured":"Xu, D. et al. The cGAS-STING Pathway: Novel Perspectives in Liver Diseases [J]. Front. Immunol. 12, 682736 (2021).","journal-title":"Front. Immunol."},{"issue":"5","key":"59095_CR22","doi-asserted-by":"publisher","first-page":"100324","DOI":"10.1016\/j.jhepr.2021.100324","volume":"3","author":"R Chen","year":"2021","unstructured":"Chen, R. et al. The role of cGAS-STING signalling in liver diseases [J]. JHEP Rep. 3 (5), 100324 (2021).","journal-title":"JHEP Rep."},{"issue":"6","key":"59095_CR23","doi-asserted-by":"publisher","first-page":"G655","DOI":"10.1152\/ajpgi.00326.2017","volume":"314","author":"Z Lei","year":"2018","unstructured":"Lei, Z. et al. cGAS-mediated autophagy protects the liver from ischemia-reperfusion injury independently of STING [J]. Am. J. Physiol. Gastrointest. Liver Physiol. 314 (6), G655\u2013g67 (2018).","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"59095_CR24","doi-asserted-by":"publisher","first-page":"753789","DOI":"10.3389\/fimmu.2021.753789","volume":"12","author":"I Couillin","year":"2021","unstructured":"Couillin, I. & Riteau, N. STING Signaling and Sterile Inflammation [J]. Front. Immunol. 12, 753789 (2021).","journal-title":"Front. Immunol."},{"issue":"2","key":"59095_CR25","doi-asserted-by":"publisher","first-page":"e372","DOI":"10.1002\/cpz1.372","volume":"2","author":"JD Bryant","year":"2022","unstructured":"Bryant, J. D. et al. Assessing Mitochondrial DNA Release into the Cytosol and Subsequent Activation of Innate Immune-related Pathways in Mammalian Cells [J]. Curr. Protoc. 2 (2), e372 (2022).","journal-title":"Curr. Protoc."},{"key":"59095_CR26","doi-asserted-by":"publisher","first-page":"823511","DOI":"10.3389\/fimmu.2022.823511","volume":"13","author":"Y Liu","year":"2022","unstructured":"Liu, Y. et al. Neutrophil Extracellular Traps Regulate HMGB1 Translocation and Kupffer Cell M1 Polarization During Acute Liver Transplantation Rejection [J]. Front. Immunol. 13, 823511 (2022).","journal-title":"Front. Immunol."},{"issue":"20","key":"59095_CR27","doi-asserted-by":"publisher","first-page":"e71114","DOI":"10.1096\/fj.202501996R","volume":"39","author":"Z Yang","year":"2025","unstructured":"Yang, Z. et al. The Role of cGAS-STING Pathway in Chronic Liver Diseases: Mechanisms and Therapeutic Perspectives [J]. Faseb j. 39 (20), e71114 (2025).","journal-title":"Faseb j."},{"key":"59095_CR28","doi-asserted-by":"publisher","first-page":"1231057","DOI":"10.3389\/fimmu.2023.1231057","volume":"14","author":"Z Chen","year":"2023","unstructured":"Chen, Z. et al. cGAS-STING pathway in ischemia-reperfusion injury: a potential target to improve transplantation outcomes [J]. Front. Immunol. 14, 1231057 (2023).","journal-title":"Front. Immunol."},{"issue":"6245","key":"59095_CR29","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1126\/science.aaa8064","volume":"349","author":"A Warnatsch","year":"2015","unstructured":"Warnatsch, A. et al. Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis [J]. Science 349 (6245), 316\u2013320 (2015).","journal-title":"Science"},{"issue":"9","key":"59095_CR30","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1038\/s41577-021-00524-z","volume":"21","author":"A Decout","year":"2021","unstructured":"Decout, A. et al. The cGAS-STING pathway as a therapeutic target in inflammatory diseases [J]. Nat. Rev. Immunol. 21 (9), 548\u2013569 (2021).","journal-title":"Nat. Rev. Immunol."},{"issue":"10","key":"59095_CR31","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1038\/ni.3558","volume":"17","author":"Q Chen","year":"2016","unstructured":"Chen, Q., Sun, L. & Chen, Z. J. Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing [J]. Nat. Immunol. 17 (10), 1142\u20131149 (2016).","journal-title":"Nat. Immunol."},{"issue":"3","key":"59095_CR32","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1038\/nri3399","volume":"13","author":"E Kolaczkowska","year":"2013","unstructured":"Kolaczkowska, E. & Kubes, P. Neutrophil recruitment and function in health and inflammation [J]. Nat. Rev. Immunol. 13 (3), 159\u2013175 (2013).","journal-title":"Nat. Rev. Immunol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-59095-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-59095-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-59095-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T22:48:07Z","timestamp":1789685287000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-59095-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,24]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["59095"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-59095-5","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-8822760\/v1","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,24]]},"assertion":[{"value":"8 February 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"29078"}}