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This study investigates the role of Dickkopf-related protein 2 (DKK2) in the pathophysiology of ischaemic stroke, exploring its potential as a therapeutic target.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Dickkopf-related protein 2 levels were analysed in a murine model of transient middle cerebral artery occlusion (tMCAO) and in stroke patients with large vessel occlusion undergoing endovascular treatment. The causal role of DKK2 was explored using genetic knockout and viral targeting strategies to manipulate its expression, and using pharmacological approaches to assess its therapeutic potential. Mechanistic studies focused on the regulation of DKK2 by retinoid X receptor-alpha (RXR\u03b1) and its effects on neuronal injury and blood\u2013brain barrier (BBB) integrity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Dickkopf-related protein 2 was significantly up-regulated in both the brain and serum of mice after tMCAO. Serum DKK2 levels were elevated in stroke patients with larger infarct volumes, ICH, and worse functional outcomes. In murine models, systemic or neuron-specific DKK2 overexpression exacerbated infarction, neurological deficits, and BBB disruption, while genetic ablation or monoclonal antibody-mediated inhibition of DKK2 substantially ameliorated these parameters. Mechanistically, DKK2 was up-regulated in neurons by RXR\u03b1 under ischaemia\/reperfusion conditions both in vitro and in vivo, and this contributed to neuronal death and BBB disruption through suppression of canonical Wnt signalling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Dickkopf-related protein 2 plays a critical role in the progression of ischaemic stroke by modulating neuronal survival and BBB integrity. Targeting DKK2 represents a promising therapeutic approach to ischaemic brain injury, and the observational human data extend experimental findings to human cerebrovascular pathology, suggesting translational potential.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/eurheartj\/ehaf959","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T13:13:31Z","timestamp":1762434811000},"page":"3759-3775","source":"Crossref","is-referenced-by-count":6,"title":["Dickkopf-related protein 2 impairs neurovascular Wnt signalling and worsens stroke outcome"],"prefix":"10.1093","volume":"47","author":[{"given":"Zhu","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Neurology, Affiliated Dongguan Hospital, Southern Medical University (Dongguan People\u2019s Hospital) , 78 Wandao Road, Dongguan, Guangdong 523059 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,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Fang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biomedical Imaging Science and System, Guangdong-Hong Kong Joint Laboratory for Metabolic Medicine, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , 1068 Xueyuan Avenue, Shenzhen, Guangdong 518055 ,","place":["China"]},{"name":"University of Chinese Academy of Sciences , Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueqing","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biomedical Imaging Science and System, Guangdong-Hong Kong Joint Laboratory for Metabolic Medicine, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , 1068 Xueyuan Avenue, Shenzhen, Guangdong 518055 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,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Wang","sequence":"additional","affiliation":[{"name":"Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , 1068 Xueyuan Avenue, Shenzhen, Guangdong 518055 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen-Ni","family":"Guo","sequence":"additional","affiliation":[{"name":"Stroke Center, Department of Neurology, The First Hospital of Jilin University , No. 1 Xinmin Street, Changchun, Jilin 130021 ,","place":["China"]},{"name":"Neuroscience Research Center, Department of Neurology, The First Hospital of Jilin University , No. 1 Xinmin Street, Changchun, Jilin 130021 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