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Previous studies have implicated matrix metalloproteinase 8 (MMP8) in sepsis pathogenesis. However, the role of MMP8 in maintaining endothelial barrier integrity during sepsis remains unclear. This study aimed to investigate the role of MMP8 in sepsis-induced vascular leakage and the underlying mechanisms. A significant increase in MMP8 expression was observed in lipopolysaccharide (LPS)-treated endothelial cells and lung tissues from mice with cecum ligation and puncture-induced sepsis. In vitro, loss- or gain-of-function of MMP8 in endothelial cells modulated LPS- or Cytomix (TNF-\u03b1, IL-1\u03b2 and IFN-\u03b3)-induced endothelial hyperpermeability, without inducing cell apoptosis or affecting cell viability. In vivo, pharmacologic inhibition of MMP8 alleviated pulmonary vascular leakage, multi-organ injury, and mortality in septic mice. Mechanistically, MMP8 interacted with ERK, promoting its phosphorylation, and consequently activated calpains, leading to membrane VE-cadherin proteolysis. This induced VE-cadherin internalisation through clathrin- and caveolin 1-mediated endocytosis. Clinically, serum MMP8 levels were elevated in patients with sepsis, with the highest levels observed in those with pleural effusion. A nomogram incorporating albumin, blood urea nitrogen, lactate, Acute Physiology and Chronic Health Evaluation II score, and serum MMP8 levels showed favourable prediction accuracy and clinical utility for pleural effusion risk. These findings suggest the critical role of MMP8 in sepsis and its potential as a promising biomarker of sepsis-induced pulmonary vascular leakage.<\/jats:p>","DOI":"10.1186\/s43556-026-00522-4","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T09:49:13Z","timestamp":1784886553000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MMP8 exacerbates sepsis-induced pulmonary vascular leakage by disruption of endothelial VE-cadherin through ERK signalling"],"prefix":"10.1186","volume":"7","author":[{"given":"Yaojun","family":"Peng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiyan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Jing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8285-4226","authenticated-orcid":false,"given":"Haiyan","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"issue":"22","key":"522_CR1","doi-asserted-by":"publisher","first-page":"2133","DOI":"10.1056\/NEJMra2403213","volume":"391","author":"NJ Meyer","year":"2024","unstructured":"Meyer NJ, Prescott HC. 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