{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:07:07Z","timestamp":1789981627110,"version":"4.0.1"},"reference-count":74,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2018YFC1707400"],"award-info":[{"award-number":["2018YFC1707400"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82205101"],"award-info":[{"award-number":["82205101"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Brain and Behavior"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The aim was to investigate the potential therapeutic targets for ischemic stroke (IS) and vascular dementia (VD).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We assessed the causal effects of 2943 plasma proteins on IS and VD using a two\u2010sample Mendelian randomization (MR) framework. Results were validated via summary data\u2010based MR (SMR) analysis. A two\u2010step mediation MR analysis was conducted to elucidate potential causal mechanisms by which plasma proteins influence IS and VD through risk factors. We performed a phenome\u2010wide association study (PheWAS) MR analysis to explore side effects and additional indications for IS and VD\u2010associated plasma proteins. We established middle cerebral artery occlusion and reperfusion (MCAO\/R) and VD rat models to verify potential therapeutic targets for IS and VD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Genetically predicted plasma levels of six proteins demonstrated causal relationships with both IS and VD. SMR analysis validated four of these proteins (CD40, F11, F2, and Furin). Atrial fibrillation (AF), type 2 diabetes (T2D), low\u2010density lipoprotein (LDL), and diastolic blood pressure (DBP) were causally associated with the risk of IS and VD, indicating common risk factors. CD40 and Furin associations with IS and VD appeared to be mediated by AF or DBP. The mechanisms of action of IS\u2010 and VD\u2010related proteins primarily involve the complement and coagulation cascade. In vivo experiments confirmed that CD40, Furin, F11, and integrin alpha\u2010V (ITGAV) were causally associated with IS and VD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings illuminate causal pathways and potential therapeutic targets for IS and VD. We identified six plasma proteins with causal relationships to IS, VD, and their risk factors, providing insights into using these proteins as therapeutic targets for IS and VD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/brb3.71096","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T07:12:02Z","timestamp":1764141122000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of Six Potential Therapeutic Targets Common to Ischemic Stroke and Vascular Dementia: Genetic Insights From an Integrated Bioinformatics Analysis"],"prefix":"10.1002","volume":"15","author":[{"given":"Jian","family":"Lyu","sequence":"first","affiliation":[{"name":"NMPA Key Laboratory for Clinical Research and Evaluation of Traditional Chinese Medicine &amp; National Clinical Research Center for Chinese Medicine Cardiology, XiYuan Hospital China Academy of Chinese Medical Sciences  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