{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T00:52:26Z","timestamp":1782607946136,"version":"3.54.5"},"reference-count":44,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T00:00:00Z","timestamp":1774742400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China\n              https:\/\/ror.org\/01h0zpd94","award":["81873180"],"award-info":[{"award-number":["81873180"]}]},{"name":"Hebei Province Natural Science Foundation Project","award":["H2022423382"],"award-info":[{"award-number":["H2022423382"]}]},{"name":"Joint Key Project of Traditional Chinese Medicine, Hebei Provincial Natural Science Foundation","award":["H2025423053"],"award-info":[{"award-number":["H2025423053"]}]},{"name":"Hebei Provincial Administration of Traditional Chinese Medicine Scientific Research Program","award":["2021101"],"award-info":[{"award-number":["2021101"]}]},{"name":"Yanzhao Medical Research Project, Hebei University of Chinese Medicine\n              https:\/\/ror.org\/02qxkhm81","award":["YZZQ2022002"],"award-info":[{"award-number":["YZZQ2022002"]}]},{"name":"Basic Scientific Research Business Funds of Provincial Universities of Hebei University of Chinese Medicine","award":["TDZR2024010"],"award-info":[{"award-number":["TDZR2024010"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Neuronal apoptosis is the core pathological mechanism of cerebral ischemic\u2013reperfusion injury (CIRI); although Astragaloside IV (AS-IV) has demonstrated neuroprotective activity against CIRI, its specific molecular mechanisms underlying the regulation of this apoptosis-related pathway remain to be systematically elucidated. Methods: We establish an in vivo model of middle cerebral artery occlusion\/reperfusion (MCAO\/R) in rats and an in vitro model of oxygen\u2013glucose deprivation\/reperfusion (OGD\/R) in PC12 cells. Six core apoptotic proteins, including CytC, Apaf-1, BAX, Bcl-2, Caspase3, and Caspase9, were detected using neurological function scoring, TTC\/HE\/Nissl staining, TUNEL staining, Western blot, and immunofluorescence techniques. Molecular docking and molecular dynamics simulation were utilized to analyze the binding affinity between AS-IV and the aforementioned apoptotic proteins. Results: Molecular docking and dynamics simulation demonstrated AS-IV stably binds six core apoptotic proteins, and comparative analysis with target-specific reference ligands identified Apaf-1 as its primary target with the most favorable binding properties. In rat MCAO\/R models, AS-IV alleviated neurological deficits, reduced cerebral infarct volume and improved brain pathological damage; in PC12 cell OGD\/R models, it decreased neuronal apoptosis. Western blot and immunofluorescence confirmed AS-IV downregulated pro-apoptotic proteins (cytoplasmic CytC, Apaf-1, BAX, cleaved-Caspase9\/3) and upregulated anti-apoptotic Bcl-2. Conclusions: This study clarifies the anti-apoptotic molecular mechanism of AS-IV, it alleviates CIRI by targeting the CytC\/Apaf-1 mitochondrial apoptotic pathway.<\/jats:p>","DOI":"10.3390\/ph19040547","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T13:41:03Z","timestamp":1774878063000},"page":"547","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Mechanism of Astragaloside IV Against Cerebral Ischemia\u2013Reperfusion Injury: Inhibiting Neuronal Apoptosis via the CytC\/Apaf-1 Mitochondrial Pathway"],"prefix":"10.3390","volume":"19","author":[{"given":"Tongtong","family":"He","sequence":"first","affiliation":[{"name":"Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine, No. 3 Xingyuan Road, Luquan District, Shijiazhuang 050200, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Zhang","sequence":"additional","affiliation":[{"name":"Traditional Chinese Medicine Program, Graduate School, Juquan Campus, Hebei University of Chinese Medicine, No. 326, Xinshinan Road, Qiaoxi District, Shijiazhuang 050091, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine, No. 3 Xingyuan Road, Luquan District, Shijiazhuang 050200, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Gao","sequence":"additional","affiliation":[{"name":"Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine, No. 3 Xingyuan Road, Luquan District, Shijiazhuang 050200, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyi","family":"Liu","sequence":"additional","affiliation":[{"name":"Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine, No. 3 Xingyuan Road, Luquan District, Shijiazhuang 050200, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanmeng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine, No. 3 Xingyuan Road, Luquan District, Shijiazhuang 050200, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Liang","sequence":"additional","affiliation":[{"name":"Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine, No. 3 Xingyuan Road, Luquan District, Shijiazhuang 050200, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijuan","family":"Gao","sequence":"additional","affiliation":[{"name":"Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine, No. 3 Xingyuan Road, Luquan District, Shijiazhuang 050200, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofei","family":"Jin","sequence":"additional","affiliation":[{"name":"Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine, No. 3 Xingyuan Road, Luquan District, Shijiazhuang 050200, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"103406","DOI":"10.1016\/j.redox.2024.103406","article-title":"Isoliquiritigenin alleviates cerebral ischemia-reperfusion injury by reducing oxidative stress and ameliorating mitochondrial dysfunction via activating the Nrf2 pathway","volume":"77","author":"Lan","year":"2024","journal-title":"Redox Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"156626","DOI":"10.1016\/j.phymed.2025.156626","article-title":"Naoqing formula alleviates cerebral ischemia\/reperfusion injury induced inflammatory injury by regulating Csf3 mediated JAK\/STAT pathway and macrophage polarization","volume":"140","author":"Ye","year":"2025","journal-title":"Phytomedicine"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e70340","DOI":"10.1111\/jcmm.70340","article-title":"Mechanism of Formononetin in Improving Energy Metabolism and Alleviating Neuronal Injury in CIRI Based on Nontargeted Metabolomics Research","volume":"29","author":"Zhao","year":"2025","journal-title":"J. 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