{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T22:18:12Z","timestamp":1790201892132,"version":"4.1.0"},"reference-count":38,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T00:00:00Z","timestamp":1764460800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003787","name":"Natural Science Foundation of Hebei Province","doi-asserted-by":"publisher","award":["H2024206168"],"award-info":[{"award-number":["H2024206168"]}],"id":[{"id":"10.13039\/501100003787","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82101378"],"award-info":[{"award-number":["82101378"]}],"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":[[2025,12]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n \n Mitochondrial dysfunction is an initial event of the cascade reactions triggered by ischemic stroke, contributing to the pathogenesis of ischemic brain injury.\n DL<\/jats:styled-content>\n \u20103\u2010n\u2010butylphthalide (\n NBP<\/jats:styled-content>\n ), a compound originally isolated from the seeds of\n \n Apium graveolens<\/jats:italic>\n <\/jats:styled-content>\n Linn, exerts neuroprotective effects by improving mitochondrial function in ischemic brain tissues; however, the exact molecular mechanisms underlying its action remain poorly understood.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n The\n OGD<\/jats:styled-content>\n \u2010exposed neuronal cells and\n dMCAO<\/jats:styled-content>\n mice were used to investigate the effects of ischemia\/hypoxia on mitochondrial function and the protective action of\n NBP<\/jats:styled-content>\n on mitochondrial damage. Co\u2010immunoprecipitation and immunofluorescence staining were performed to identify the interaction between Drp1 and\n GCN5L1<\/jats:styled-content>\n . Western blotting, immunofluorescence and immunohistochemical staining were conducted to detect the expression of\n GCN5L1<\/jats:styled-content>\n , Drp1,\n ERK1<\/jats:styled-content>\n \/2, Bax, Bcl2, and caspase\u20103. The mitochondrial function was analyzed by measuring mitochondrial\n ROS<\/jats:styled-content>\n ,\n ATP<\/jats:styled-content>\n production, mitochondrial membrane potential (\n MMP<\/jats:styled-content>\n ) and\n mPTP<\/jats:styled-content>\n opening.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n We observed that mitochondrial dysfunction occurs in\n OGD<\/jats:styled-content>\n \u2010treated neuronal cells and brain tissues of\n dMCAO<\/jats:styled-content>\n mice, as evidenced by the alteration in the\n mPTP<\/jats:styled-content>\n ,\n MMP<\/jats:styled-content>\n ,\n ATP<\/jats:styled-content>\n content, and\n ROS<\/jats:styled-content>\n levels, which are accompanied by a significant increase in mitochondrial fission and neuronal apoptosis, as shown by\n TUNEL<\/jats:styled-content>\n staining and the changes in Bcl\u20102, Bax and caspase\u20103 expression. Importantly,\n NBP<\/jats:styled-content>\n intervention significantly attenuates ischemia\/hypoxia\u2010induced mitochondrial dysfunction and cellular apoptosis in the neuron and mouse brains. Mechanistically,\n NBP<\/jats:styled-content>\n not only reverses the upregulation of Drp1 and\n GCN5L1<\/jats:styled-content>\n expression by ischemia\/hypoxia, but also inhibits the ischemia\/hypoxia\u2010induced phosphorylation of Drp1 by blocking the\n ERK1<\/jats:styled-content>\n \/2 signaling, which in turn suppresses the interaction between Drp1 and\n GCN5L1<\/jats:styled-content>\n , thereby decreasing Drp1 acetylation by\n GCN5L1<\/jats:styled-content>\n and excessive mitochondrial fission.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Our findings provide a novel insight into the molecular mechanism whereby\n NBP<\/jats:styled-content>\n protects mitochondria against ischemia\/hypoxia damage, offering a promising drug for mitochondria\u2010targeting therapeutics for ischemic stroke.\n <\/jats:p>\n 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