{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T04:53:41Z","timestamp":1775883221824,"version":"3.50.1"},"reference-count":164,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,14]],"date-time":"2025-12-14T00:00:00Z","timestamp":1765670400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Newborn Brain Society"},{"DOI":"10.13039\/501100001505","name":"Health Research Council of New Zealand","doi-asserted-by":"crossref","award":["22\/559"],"award-info":[{"award-number":["22\/559"]}],"id":[{"id":"10.13039\/501100001505","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Hypoxic\u2013ischaemic encephalopathy (HIE) is a major cause of neonatal brain injury and is associated with a high rate of death and lifelong disability. Its pathogenesis is still poorly understood, and there is no proven treatment for preterm infants. Therapeutic hypothermia for term and near-term infants partially improves outcomes, highlighting the need to target additional mechanisms. This review evaluates evidence that necrosis and necroptosis contribute materially to evolving brain injury in both term and preterm brains. Serial imaging studies suggest that lesions typically develop over many days after birth for term infants and over many weeks after birth for preterm infants. Growing evidence from animal studies shows that severe white matter injury can be mediated by programmed necroptosis. In particular, lesions that evolve late after acute HI are characterised by necrosis in association with agglomerations of microglia, with little apoptotic cell death. Critically, preclinical studies in large and small animals show that outcomes can be dramatically improved by very delayed intervention after HI including with cell therapy, anti-inflammatory agents, and endogenous neurotrophins. These findings strongly support the hypothesis that there may be a window of therapeutic opportunity for days or even weeks after birth to prevent delayed necrotic lesions.<\/jats:p>","DOI":"10.3390\/cells14241984","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T10:11:23Z","timestamp":1765793483000},"page":"1984","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Potential Clinical Relevance of Necrosis\u2013Necroptosis Pathways for Hypoxic\u2013Ischaemic Encephalopathy"],"prefix":"10.3390","volume":"14","author":[{"given":"Benjamin A.","family":"Lear","sequence":"first","affiliation":[{"name":"Department of Physiology, The University of Auckland, Auckland 1010, New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5062-9849","authenticated-orcid":false,"given":"Alice J.","family":"McDouall","sequence":"additional","affiliation":[{"name":"Department of Physiology, The University of Auckland, Auckland 1010, New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivia J.","family":"Lear","sequence":"additional","affiliation":[{"name":"Department of Physiology, The University of Auckland, Auckland 1010, New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simerdeep K.","family":"Dhillon","sequence":"additional","affiliation":[{"name":"Department of Physiology, The University of Auckland, Auckland 1010, New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8937-0846","authenticated-orcid":false,"given":"Christopher A.","family":"Lear","sequence":"additional","affiliation":[{"name":"Department of Physiology, The University of Auckland, Auckland 1010, New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4557-2646","authenticated-orcid":false,"given":"Frances J.","family":"Northington","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Bennet","sequence":"additional","affiliation":[{"name":"Department of Physiology, The University of Auckland, Auckland 1010, New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0656-7035","authenticated-orcid":false,"given":"Alistair J.","family":"Gunn","sequence":"additional","affiliation":[{"name":"Department of Physiology, The University of Auckland, Auckland 1010, New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/pr.2013.206","article-title":"Intrapartum-related neonatal encephalopathy incidence and impairment at regional and global levels for 2010 with trends from 1990","volume":"74","author":"Lee","year":"2013","journal-title":"Pediatr. 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