{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T22:22:14Z","timestamp":1787955734813,"version":"build-2784847793"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T00:00:00Z","timestamp":1753142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Neutrophil extracellular traps (NETs) play a critical role in inflammation and coagulation imbalance. Recent studies have demonstrated that activation of gasdermin D (GSDMD) protein and its pore-forming activity are essential drivers of NET generation. This study investigated the association between GSDMD-NETs axis activation and sepsis-induced coagulopathy (SIC), as well as the potential association with glycocalyx damage.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>A prospective cohort of 70 sepsis patients (35 with SIC, 35 non-SIC) admitted to a respiratory intensive care unit was analyzed. This study was registered at the Chinese Clinical Trial Registry (ChiCTR) with the registration number ChiCTR2500100284. The trial can be accessed at <jats:uri>https:\/\/www.chictr.org.cn\/bin\/project\/edit?pid=266738<\/jats:uri>. Plasma levels of GSDMD-NETs biomarkers (N-GSDMD, MPO-DNA) and glycocalyx injury markers (syndecan-1, MMP-9) were measured via ELISA. Clinical outcomes, thrombotic\/hemorrhagic events, and biomarker correlations were evaluated using logistic regression, ROC analysis, and Pearson\u2019s correlation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared to non-SIC patients, the SIC group exhibited higher rates of viral infections (31.4% <jats:italic>vs<\/jats:italic>. 11.4%, P = 0.043), hemorrhagic events (48.6% <jats:italic>vs<\/jats:italic>. 17.1%, P = 0.005), and in-hospital mortality (40.0% <jats:italic>vs<\/jats:italic>. 17.1%, P = 0.034). SIC patients demonstrated significantly elevated GSDMD-NETs axis biomarkers (N-GSDMD: 481.302 <jats:italic>vs<\/jats:italic>. 539.033, P &amp;lt; 0.001; MPO-DNA: 376.708 <jats:italic>vs<\/jats:italic>. 461.847, P &amp;lt; 0.001) and glycocalyx damage markers (syndecan-1: 367.754 <jats:italic>vs<\/jats:italic>. 431.186, P=&amp;lt; 0.001; MMP-9: 121.550 <jats:italic>vs<\/jats:italic>. 133.931, p = 0.009). GSDMD-NETs biomarkers independently predicted SIC risk (MPO-DNA: OR 1.015, 95% CI 1.005\u20131.025; N-GSDMD: OR 1.018, 95% CI 1.005\u20131.031). ROC analysis revealed predictive efficacy for SIC (N-GSDMD: AUC 0.786; MPO-DNA: AUC 0.772), with enhanced performance for their combination (AUC: 0.859). Similarly, the combined biomarkers predicted mechanical ventilation (AUC: 0.755) and mortality (AUC: 0.767). MPO-DNA correlated with syndecan-1 (r = 0.856, p &amp;lt; 0.001) and MMP-9 (r = 0.595, p &amp;lt; 0.001), while N-GSDMD correlated with syndecan-1 (r = 0.343, p = 0.004) and MMP-9 (r = 0.509, p = 0.042).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The activation of the GSDMD-NETs axis is strongly associated with the development of SIC, glycocalyx injury, and adverse clinical outcomes in sepsis, potentially contributing to these pathological processes. Plasma N-GSDMD and MPO-DNA serve as predictive biomarkers for SIC severity and mortality, highlighting their potential role in targeted therapeutic strategies.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1624128","type":"journal-article","created":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T05:31:31Z","timestamp":1753162291000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["GSDMD-NETs in patients with sepsis-induced coagulopathy and their interaction with glycocalyx 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