{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T07:21:53Z","timestamp":1792480913040,"version":"4.5.0"},"reference-count":56,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,6,8]],"date-time":"2025-06-08T00:00:00Z","timestamp":1749340800000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82271507"],"award-info":[{"award-number":["82271507"]}],"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":["82171190"],"award-info":[{"award-number":["82171190"]}],"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":["81873924"],"award-info":[{"award-number":["81873924"]}],"id":[{"id":"10.13039\/501100001809","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":[[2025,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Aim<\/jats:title><jats:p>White matter injury (WMI), characterized by white matter degeneration and iron deposition, contributes to neurological dysfunction. Histone deacetylase 3 (HDAC3) is implicated in neurodegenerative processes, yet its role in WMI\u2010associated ferroptosis remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Clinical assessments in WMI patients revealed correlations between serum iron, \u03b1\u2010synuclein, and antioxidant levels and MRI\u2010confirmed white matter degeneration. In a cuprizone\u2010induced demyelination mouse model, white matter integrity, oligodendrocyte dysfunction, iron accumulation, and lipid peroxidation were evaluated through behavioral testing, histological staining, and biochemical analyses. To identify potential molecular targets of HDAC3\u2010mediated ferroptosis, CUT&amp;Tag sequencing was performed. The involvement of this pathway was further validated in\u00a0vitro using iron overload assays and in\u00a0vivo through HDAC3 overexpression via AAV vectors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the present study, HDAC3 expression was elevated following demyelination and was suppressed by RGFP966 treatment. Brain MRI findings from clinical patients and histological analyses in CPZ\u2010treated mice revealed disrupted iron metabolism following white matter injury, likely driven by increased iron deposition and lipid peroxidation in the affected regions. HDAC3 inhibition alleviated oligodendrocyte lineage dysfunction, preserved myelin integrity, and mitigated cognitive and motor deficits induced by demyelination. CUT&amp;Tag sequencing suggested that the therapeutic effects of RGFP966 are mediated through HDAC3\u2010dependent regulation of ferroptosis. The reliability of these findings was further supported by in\u00a0vivo validation of ferroptosis\u2010related gene expression, indicating that the HDAC3\u2013pyruvate dehydrogenase kinase 4 (PDK4) axis plays a critical role in the epigenetic regulation of ferroptosis\u2010related pathways.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>HDAC3 drives ferroptosis in WMI via iron metabolism and lipid peroxidation, highlighting the HDAC3\u2010PDK4 axis as a therapeutic target.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.70471","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T11:01:01Z","timestamp":1749726061000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Targeting HDAC3 Suppresses Ferroptosis and Demyelination in White Matter Injury by Restoring PDK4\u2010Mediated Iron Homeostasis"],"prefix":"10.1111","volume":"31","author":[{"given":"Ting","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Neurophysiology and Neuropharmacology, Institute of Special Environmental Medicine and Co\u2010Innovation Center of Neuroregeneration Nantong University  Nantong Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisha","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Neurophysiology and Neuropharmacology, Institute of Special Environmental Medicine and Co\u2010Innovation Center of Neuroregeneration Nantong University  Nantong Jiangsu China"},{"name":"Department of Neurology Xuanwu Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenfeng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurophysiology and Neuropharmacology, Institute of Special Environmental Medicine and Co\u2010Innovation Center of Neuroregeneration Nantong University  Nantong Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangming","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurophysiology and Neuropharmacology, Institute of Special Environmental Medicine and Co\u2010Innovation Center of Neuroregeneration Nantong University  Nantong Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianjiao","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Neurophysiology and Neuropharmacology, Institute of Special Environmental Medicine and Co\u2010Innovation Center of Neuroregeneration Nantong University  Nantong Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhui","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Neurophysiology and Neuropharmacology, Institute of Special Environmental Medicine and Co\u2010Innovation Center of Neuroregeneration Nantong University  Nantong Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihua","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Neurophysiology and Neuropharmacology, Institute of Special Environmental Medicine and Co\u2010Innovation Center of Neuroregeneration Nantong University  Nantong Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingde","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Neurology Xuanwu Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Neurophysiology and Neuropharmacology, Institute of Special Environmental Medicine and Co\u2010Innovation Center of Neuroregeneration Nantong University  Nantong Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0494-416X","authenticated-orcid":false,"given":"Chuanjie","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Neurology Xuanwu Hospital Capital Medical University  Beijing China"},{"name":"Beijing Institute of Brain Disorders Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4810-8534","authenticated-orcid":false,"given":"Guohua","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology Xuanwu Hospital Capital Medical University  Beijing China"},{"name":"Beijing Institute of Brain Disorders Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,8]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nicl.2022.103096"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac359"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.07.027"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-024-01428-1"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/cns.13497"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2023.10.018"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-802395-2.00019-5"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2018.02.006"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000207664"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.24238"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-022-01170-x"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12310"},{"issue":"20","key":"e_1_2_10_14_1","first-page":"3614","article-title":"Transferrin Receptor Is Necessary for Proper Oligodendrocyte Iron Homeostasis and Development","volume":"43","author":"Cheli V. T.","year":"2023","journal-title":"Journal of Neuroscience"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1137635"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2022.577995"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1177\/1759091420962681"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom12050714"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-00324-8"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2024.105788"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26770"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-022-00468-7"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.1c00463"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.acc.2020.09.004"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.2174\/1570159X22666240128002056"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.2174\/1570159X19666210609160017"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2020.117278"},{"key":"e_1_2_10_28_1","article-title":"HDAC3 as an Emerging Therapeutic Target for Alzheimer's Disease and Other Neurological Disorders","author":"Li Y.","year":"2025","journal-title":"Molecular Neurobiology"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-020-02060-8"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-022-02782-x"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/burnst\/tkad062"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2023.102939"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep07458"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.1c00826"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2018.05.024"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2021.06.007"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-020-02277-7"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-49202-3"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.83543"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-5728(98)00168-4"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1749-20.2020"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23538"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-022-02563-2"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2023.04.003"},{"issue":"3","key":"e_1_2_10_45_1","first-page":"206","article-title":"HDAC Inhibitors Mitigate Ischemia\u2010Induced Oligodendrocyte Damage: Potential Roles of Oligodendrogenesis, VEGF, and Anti\u2010Inflammation","volume":"6","author":"Kim H. J.","year":"2014","journal-title":"American Journal of Translational Research"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-021-00742-3"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12366"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2023.110429"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-020-03599-4"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1111\/cns.14865"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00500-z"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2023.e18160"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.108767"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2024.111282"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-023-01725-2"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.4093\/dmj.2023.0196"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29902"}],"container-title":["CNS Neuroscience &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cns.70471","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T09:30:56Z","timestamp":1754904656000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cns.70471"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6]]},"references-count":56,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,6]]}},"alternative-id":["10.1111\/cns.70471"],"URL":"https:\/\/doi.org\/10.1111\/cns.70471","archive":["Portico"],"relation":{},"ISSN":["1755-5930","1755-5949"],"issn-type":[{"value":"1755-5930","type":"print"},{"value":"1755-5949","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6]]},"assertion":[{"value":"2025-03-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70471"}}