{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T10:24:51Z","timestamp":1787653491926,"version":"build-2736575974"},"reference-count":36,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Chongqing Municipal Training Program of Innovation and Entrepreneurship for Undergraduates","award":["s202410631056"],"award-info":[{"award-number":["s202410631056"]}]},{"name":"Chongqing Science Technology Commission","award":["CSTB2022NSCQ-MSX1097"],"award-info":[{"award-number":["CSTB2022NSCQ-MSX1097"]}]},{"DOI":"10.13039\/501100007957","name":"Chongqing Municipal Education Commission","doi-asserted-by":"publisher","award":["KJQN202200458"],"award-info":[{"award-number":["KJQN202200458"]}],"id":[{"id":"10.13039\/501100007957","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation Project","doi-asserted-by":"publisher","award":["2022MD713710"],"award-info":[{"award-number":["2022MD713710"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2022MD713710"],"award-info":[{"award-number":["2022MD713710"]}],"id":[{"id":"https:\/\/ror.org\/0426zh255","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Chongqing Postdoctoral Special Funding of Chongqing Human Resources and Social Security Bureau","award":["2021XM3063"],"award-info":[{"award-number":["2021XM3063"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Cerebral ischemia\u2013reperfusion injury (CIRI) poses therapeutic challenges because of oxidative stress, blood\u2013brain barrier disruption, and neuronal apoptosis, limiting current treatments. Paeoniflorin (PF) from Paeonia lactiflora has neuroprotective potential, but its multi-target mechanisms remain unclear. This study investigated the role and mechanisms of PF in CIRI, focusing on neuron\u2013endothelial crosstalk. Methods: Oxygen\u2013glucose deprivation\/reoxygenation (OGD\/R) models were established using SH-SY5Y (human neuroblastoma) and HCMEC\/D3 cells (human cerebral microvascular endothelial). Network pharmacology was used to predict potential PF targets and pathways. RNA sequencing, molecular docking, and molecular dynamics simulation were performed to screen and evaluate PF binding characteristics with key targets, and MTT, flow cytometry, Western blotting, and co-cultures were employed to detect paracrine interactions. Results: Network pharmacology and transcriptomics identified VEGF\/PI3K-AKT\/mTOR pathway enrichment. Molecular docking confirmed stable PF binding to VEGF-A (\u22128.4 kcal\/mol), AKT (\u22125.5 kcal\/mol), and mTOR (\u22129.6 kcal\/mol). PF (10\u201380 \u03bcM) showed no cytotoxicity and reduced OGD\/R injury in a concentration-dependent manner (maximal at 40 \u03bcM). PF activated VEGF\/PI3K-AKT\/mTOR signaling, reducing apoptosis by 57% (SH-SY5Y) and 33% (HCMEC\/D3); PI3K inhibitor LY294002 abolished these effects. PF-treated HCMEC\/D3-conditioned media enhanced OGD\/R neuronal viability, verifying paracrine crosstalk. Conclusions: PF alleviated CIRI by directly protecting neurons and indirectly modulating neuron\u2013endothelial crosstalk through VEGF\/PI3K-AKT\/mTOR activation, supporting its multi-target therapeutic potential.<\/jats:p>","DOI":"10.3390\/ph19091339","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T13:20:43Z","timestamp":1787577643000},"page":"1339","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Paeoniflorin Alleviates Oxygen\u2013Glucose Deprivation\/Reoxygenation Injury by Mediating Crosstalk Between Neurons and Endothelial Cells Through the VEGF\/PI3K-AKT\/mTOR Pathway"],"prefix":"10.3390","volume":"19","author":[{"given":"Zike","family":"Xu","sequence":"first","affiliation":[{"name":"Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxia","family":"Luo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuhui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The Second Afffliated Hospital of Chongqing Medical University, 76 Linjiang Road, Chongqing 400010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sha","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1177\/17474930241308142","article-title":"World Stroke Organization: Global Stroke Fact Sheet 2025","volume":"20","author":"Feigin","year":"2025","journal-title":"Int. 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