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The impact of <jats:italic>DNMT3A<\/jats:italic>, the most mutated gene in CHIP, on clinical functional outcomes of acute ischemic stroke (AIS) remains unclear. In a well\u2010characterized cohort of 8524 ischemic stroke patients, we demonstrated that <jats:italic>DNMT3A<\/jats:italic>\u2010driven CHIP was significantly associated with neurological disability in these patients. With a stroke mouse model of transient middle cerebral artery occlusion (tMCAO), we demonstrated that DNMT3A protein levels in the brain penumbra increased. The DNMT3A inhibitor RG108 administration amplified neutrophil proliferation in the blood, promoted neutrophil infiltration into the brain penumbra, and exaggerated proinflammatory activation in tMCAO male mice. DNMT3A inhibition also significantly increased infarct volume and worsened neurobehavioral function in tMCAO male mice. In conclusion, <jats:italic>DNMT3A<\/jats:italic> somatic mutations are associated with worsened neurological disability in some patients with AIS, potentially through increased neutrophil proliferation and infiltration in the ischemic brain region. These findings suggest a possible mechanism for proinflammatory activation and tissue damage in the affected brain tissue, highlighting the need for further research in this area.<\/jats:p>","DOI":"10.1002\/mco2.652","type":"journal-article","created":{"date-parts":[[2024,7,14]],"date-time":"2024-07-14T14:45:51Z","timestamp":1720968351000},"source":"Crossref","is-referenced-by-count":11,"title":["DNMT3A dysfunction promotes neuroinflammation and exacerbates acute ischemic stroke"],"prefix":"10.1002","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1934-8643","authenticated-orcid":false,"given":"Tian\u2010Jie","family":"Lyu","sequence":"first","affiliation":[{"name":"Department of Neurology Beijing Tiantan Hospital Capital Medical University  Beijing China"},{"name":"China National Clinical Research Center for Neurological Diseases  Beijing 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