{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T17:44:55Z","timestamp":1782323095578,"version":"3.54.5"},"reference-count":60,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2024,12,8]],"date-time":"2024-12-08T00:00:00Z","timestamp":1733616000000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["LI\u20102534\/6\u20101"],"award-info":[{"award-number":["LI\u20102534\/6\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["LI\u20102534\/7\u20101"],"award-info":[{"award-number":["LI\u20102534\/7\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82371317"],"award-info":[{"award-number":["82371317"]}],"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":["82071290"],"award-info":[{"award-number":["82071290"]}],"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":["82171279"],"award-info":[{"award-number":["82171279"]}],"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":["M\u20100671"],"award-info":[{"award-number":["M\u20100671"]}],"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":["U22A20295"],"award-info":[{"award-number":["U22A20295"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018625","name":"Science and Technology Innovation Plan Of Shanghai Science and Technology Commission","doi-asserted-by":"publisher","award":["201409002500"],"award-info":[{"award-number":["201409002500"]}],"id":[{"id":"10.13039\/501100018625","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":[[2024,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Aim<\/jats:title><jats:p>Hyperlipidemia is a common comorbidity of stroke patients, elucidating the mechanism that underlies the exacerbated ischemic brain injury after stroke with hyperlipidemia is emerging as a significant clinical problem due to the growing proportion of hyperlipidemic stroke patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Mice were fed a high\u2010fat diet for 12\u2009weeks to induce hyperlipidemia. Transient middle cerebral artery occlusion was induced as a mouse model of ischemic stroke. <jats:italic>Emx1<\/jats:italic><jats:sup><jats:italic>Cre<\/jats:italic><\/jats:sup> mice were crossed with <jats:italic>Mef2c<\/jats:italic><jats:sup><jats:italic>fl\/fl<\/jats:italic><\/jats:sup> mice to specifically deplete Mef2c in neurons.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We reported that hyperlipidemia significantly aggravated neuronal necroptosis and exacerbated long\u2010term neurological deficits following ischemic stroke in mice. Mechanistically, Cflar, an upstream necroptotic regulator, was alternatively spliced into pro\u2010necroptotic isoform (Cflar<jats:sub>R<\/jats:sub>) in ischemic neurons of hyperlipidemic mice. Neuronal Mef2c was a transcription factor modulating Cflar splicing and upregulated by hyperlipidemia following stroke. Neuronal specific Mef2c depletion reduced cerebral level of Cflar<jats:sub>R<\/jats:sub> and cFLIP<jats:sub>R<\/jats:sub> (translated by Cflar<jats:sub>R<\/jats:sub>), while mitigated neuron necroptosis and neurological deficits following stroke in hyperlipidemic mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our study highlights the pathogenic role of Cflar<jats:sub>R<\/jats:sub> splicing mediated by neuronal Mef2c, which aggravates neuron necroptosis following stroke with comorbid hyperlipidemia and proposes Cflar<jats:sub>R<\/jats:sub> splicing as a potential therapeutic target for hyperlipidemic stroke patients.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.70144","type":"journal-article","created":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T07:25:32Z","timestamp":1733729132000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Mef2c Exacerbates Neuron Necroptosis via Modulating Alternative Splicing of Cflar in Ischemic Stroke With Hyperlipidemia"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5878-2621","authenticated-orcid":false,"given":"Ruqi","family":"Li","sequence":"first","affiliation":[{"name":"Cerebrovascular Diseases Center, Department of Neurosurgery Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianchen","family":"Huang","sequence":"additional","affiliation":[{"name":"Cerebrovascular Diseases Center, Department of Neurosurgery Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianpo","family":"Zhou","sequence":"additional","affiliation":[{"name":"Cerebrovascular Diseases Center, Department of Neurosurgery Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiansheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Cerebrovascular Diseases Center, Department of Neurosurgery Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gan","family":"Li","sequence":"additional","affiliation":[{"name":"Cerebrovascular Diseases Center, Department of Neurosurgery Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueman","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Key Laboratory of the Ministry of Education Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"Clinical Research Center Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6073-5947","authenticated-orcid":false,"given":"Yunlu","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Key Laboratory of the Ministry of Education Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"Clinical Research Center Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengshi","family":"Li","sequence":"additional","affiliation":[{"name":"Cerebrovascular Diseases Center, Department of Neurosurgery Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Key Laboratory of the Ministry of Education Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"Clinical Research Center Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"Liesz","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital, LMU  Munich Germany"},{"name":"Munich Cluster for Systems Neurology (SyNergy)  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5721-9914","authenticated-orcid":false,"given":"Peiying","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Key Laboratory of the Ministry of Education Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"Clinical Research Center Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenghong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Key Laboratory of the Ministry of Education Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieqing","family":"Wan","sequence":"additional","affiliation":[{"name":"Cerebrovascular Diseases Center, Department of Neurosurgery Renji Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,12,8]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(21)00252-0"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000001123"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)01588-4"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)02600-9"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(14)70381-X"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1159\/000204914"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.109.555003"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.121.056805"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.111.639112"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-00630-3"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1916427117"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13814"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-018-0093-1"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio711"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.14336\/AD.2018.0728"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-02770-w"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms161226232"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201002060"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2011.06.011"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1517562113"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.2013.736499"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10571-016-0360-5"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X20943823"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-018-1237-y"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.24475"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2010.07047.x"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2023.106044"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagrm.2021.194703"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1357-2725(97)00023-X"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1080\/21691401.2019.1626408"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-06210-3"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz099"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10924"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.22.6424"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01505-09"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(95)00061-3"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2014.242"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-02-204230"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom14070749"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu12010181"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noab114"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00769-0"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-023-01315-6"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2021.105272"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.14336\/AD.2023.0219"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.16994"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-13099-4"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2013.56"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2014.594"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2012.02.021"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cr.7310073"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0802679105"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abd7695"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-020-00396-7"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.581915"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12975-019-00770-3"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202306379"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.123.044279"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X21999553"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X17746174"}],"container-title":["CNS Neuroscience &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cns.70144","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T07:36:28Z","timestamp":1736753788000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cns.70144"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12]]},"references-count":60,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2024,12]]}},"alternative-id":["10.1111\/cns.70144"],"URL":"https:\/\/doi.org\/10.1111\/cns.70144","archive":["Portico"],"relation":{},"ISSN":["1755-5930","1755-5949"],"issn-type":[{"value":"1755-5930","type":"print"},{"value":"1755-5949","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12]]},"assertion":[{"value":"2024-10-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70144"}}