{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:55:21Z","timestamp":1790751321918,"version":"4.1.0"},"reference-count":52,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32371053"],"award-info":[{"award-number":["32371053"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81973308"],"award-info":[{"award-number":["81973308"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81673416"],"award-info":[{"award-number":["81673416"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFC2705200"],"award-info":[{"award-number":["2022YFC2705200"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2026,10]]},"abstract":"ABSTRACT<\/jats:title>\n \n Objective<\/jats:title>\n Histone deacetylases are implicated in ischemic stroke, yet the role of HDAC5 remains poorly defined. This study aimed to determine the pathological significance of HDAC5 after cerebral ischemia, clarify its involvement in post\u2010ischemic NF\u2010\u03baB p65\/NLRP3 signaling, and evaluate an HDAC5\u2010targeted extracellular vesicle (EV)\u2010based therapeutic strategy.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n HDAC5 expression after ischemic injury was examined in a mouse middle cerebral artery occlusion (MCAO) model by western blotting and immunofluorescence. Its function was assessed by gain\u2010 and loss\u2010of\u2010function experiments in BV2 cells and MCAO mice. Infarct volume, cerebral blood flow, and neurological recovery were evaluated by TTC staining, magnetic resonance imaging (MRI), color Doppler imaging, and behavioral tests. Co\u2010immunoprecipitation, acetylation analysis, and cytoplasmic\/nuclear fractionation were used to explore the underlying mechanism. Human neural stem cell\u2010derived EVs loaded with miR\u20109\u20105p and modified with RGD peptide were further tested as a targeted therapeutic approach.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n HDAC5 was markedly upregulated after MCAO, localizing mainly to neurons in the ischemic core and microglia in the penumbra, together with increased NLRP3 expression. In BV2 cells, HDAC5 overexpression increased NLRP3 expression, whereas HDAC5 knockdown reduced it. In\u00a0vivo, AAV\u2010mediated HDAC5 knockdown decreased NLRP3 levels, reduced infarct volume, improved blood flow recovery, and ameliorated motor deficits after MCAO. Mechanistically, HDAC5 interacted with NF\u2010\u03baB p65 rather than NLRP3. HDAC5 knockdown increased p65 acetylation and reduced its nuclear translocation, consistent with suppression of NLRP3\u2010associated inflammatory signaling. Moreover, engineered RGD\u2010EV:miR\u20109\u20105p was efficiently taken up by microglia, suppressed HDAC5 and NLRP3 expression, and improved histological and functional outcomes after MCAO.<\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n These findings identify HDAC5 as a previously underappreciated regulator of post\u2010ischemic inflammatory injury and support a role for the HDAC5\/NF\u2010\u03baB p65\/NLRP3 axis in cerebral ischemia. Engineered RGD\u2010EV:miR\u20109\u20105p may therefore represent a promising targeted therapeutic strategy for ischemic stroke.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/cns.71161","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:00:03Z","timestamp":1790748003000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Microglial\n HDAC5<\/scp>\n Suppresses\n NLRP3<\/scp>\n Inflammation via\n NF<\/scp>\n \u2010\n \u03baB<\/scp>\n Deacetylation to Alleviate Ischemic Brain Injury"],"prefix":"10.1002","volume":"32","author":[{"given":"Ru\u2010Yu","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Science Nanjing Medical University Nanjing China"},{"name":"Center\u00a0for Novel Target and Therapeutic Intervention (CNTTI), College of Pharmacy Chongqing Medical University Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia\u2010Qi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Science Nanjing Medical University Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5002-1532","authenticated-orcid":false,"given":"Tian\u2010Yi","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Science Nanjing Medical University Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li\u2010Qing","family":"Tao","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Shanghai Stomatological Hospital & School of Stomatology Fudan University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"She","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Science Nanjing Medical University Nanjing China"},{"name":"Nantong Fourth People's Hospital Nantong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0278-4530","authenticated-orcid":false,"given":"Zhou\u2010Na","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Science Nanjing Medical University Nanjing China"},{"name":"Department of Cancer Research Center, Nantong Tumor Hospital The Affiliated Tumor Hospital of Nantong University Nantong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cui","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Science Nanjing Medical University Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5925-537X","authenticated-orcid":false,"given":"Jun","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Science Nanjing Medical University Nanjing China"},{"name":"Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Shanghai Stomatological Hospital & School of Stomatology Fudan University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/S1474-4422(21)00252-0","article-title":"Global, Regional, and National Burden of Stroke and Its Risk Factors, 1990\u20132019: A Systematic Analysis for the Global Burden of Disease Study 2019","volume":"20","author":"GBD 2019 Stroke Collaborators","year":"2021","journal-title":"Lancet Neurology"},{"key":"e_1_2_12_3_1","doi-asserted-by":"crossref","first-page":"S6","DOI":"10.1212\/WNL.0000000000012781","article-title":"Global Epidemiology of Stroke and Access to Acute Ischemic Stroke Interventions","volume":"97","author":"Saini V.","year":"2021","journal-title":"Neurology"},{"key":"e_1_2_12_4_1","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.redox.2018.03.002","article-title":"Diverse Roles of Mitochondria in Ischemic Stroke","volume":"16","author":"Yang J. 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