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When released into circulation due to cell death mechanisms such as NETosis, histones act as damage\u2010associated molecular patterns (DAMPs), contributing to excessive inflammation, endothelial dysfunction, immune response dysregulation, coagulation activation, cell death, and multi\u2010organ damage. Increasing evidence supports their role in the pathophysiology of sepsis, acute lung injury, cardiac injury, pancreatitis, and other life\u2010threatening conditions. Given their strong association with disease severity and prognosis, circulating histones have gained attention as potential clinical biomarkers for early diagnosis, prognosis, and therapeutic monitoring in critically ill patients. This review discusses the biological roles of extracellular histones, their potential as biomarkers, different approaches to measure them, and emerging therapeutic strategies aimed at neutralizing or removing circulating histones to improve patient outcomes in severe medical conditions.<\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"box\" position=\"anchor\">\n                      <jats:caption>\n                        <jats:title>Impact statement<\/jats:title>\n                      <\/jats:caption>\n                      <jats:p>This review highlights extracellular histones as key mediators and biomarkers in sepsis, proposing their use in diagnosis, prognosis, and treatment monitoring. Integrating quantitative proteomics for the detection of circulating histones may enhance patient stratification and guide therapeutic strategies, advancing personalized medicine in critical care.<\/jats:p>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1002\/1873-3468.70093","type":"journal-article","created":{"date-parts":[[2025,6,29]],"date-time":"2025-06-29T10:38:57Z","timestamp":1751193537000},"page":"3174-3195","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Circulating histones as clinical biomarkers in critically ill conditions"],"prefix":"10.1002","volume":"599","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7547-7872","authenticated-orcid":false,"given":"Jos\u00e9 Luis","family":"Garc\u00eda\u2010Gimenez","sequence":"first","affiliation":[{"name":"Department of Physiology, Faculty of Medicine and Dentistry University of Valencia  Spain"},{"name":"INCLIVA Biomedical Research Institute  Valencia Spain"},{"name":"Center for Biomedical Network Research on Rare Diseases (CIBERER) Carlos III Health Institute  Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Carlos","family":"Ruiz\u2010Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Intensive Care Department Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus  Barcelona Spain"},{"name":"Shock, Organ Dysfunction and Resuscitation Research Group. 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