{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T10:58:07Z","timestamp":1790852287092,"version":"4.1.0"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Recent studies have demonstrated that ferroptosis plays a crucial role in neuronal cell death following cerebral infarction. Our previous research showed that gastrodin (GAS) significantly improved neurological function in rats subjected to middle cerebral artery occlusion (MCAO); however, the underlying mechanisms remain unclear. In the present study, we employed Western blotting, quantitative PCR (qPCR), and immunofluorescence assays to investigate the changes in the expression levels of ferroptosis-related regulatory proteins (ACSL4, TFR1, GPX4, and MBL-2) in both\n                    <jats:italic>in vivo<\/jats:italic>\n                    and\n                    <jats:italic>in vitro<\/jats:italic>\n                    models following ischemic-hypoxic injury, as well as the modulatory effects of gastrodin on these proteins. We also conducted an in-depth exploration of an innovative therapeutic approach involving exosomes. Specifically, we constructed gastrodin-treated serum exosomes (GSE) to assess their role in neuroprotection. Our findings revealed that gastrodin significantly reduced infarct volume in middle cerebral artery occlusion rats. Compared with the model group, the levels of ACSL4, TFR1, and MBL-2 proteins were markedly decreased, while GPX4 expression was significantly upregulated in the ischemic hemisphere of the gastrodin-treated rats. These results suggest that gastrodin exerts neuroprotective effects by inhibiting ferroptosis following cerebral infarction. In an oxygen-glucose deprivation model using Neuro-2a cells, we further observed that GSE enhanced cell viability by suppressing ferroptosis. Using RNA immunoprecipitation dual-luciferase reporter assays, and fluorescence\n                    <jats:italic>in situ<\/jats:italic>\n                    hybridization we confirmed colocalization between miR-455\u20135p and ACSL4. Subsequently, we manipulated miR-455\u20135p expression in Neuro-2a cells through transfection and assessed cell viability using CCK-8 and Live\/Dead assays. The results demonstrated that GSE inhibited OGD-induced ferroptosis and improved cell viability by modulating the miR-455\u20135p\/ACSL4 signaling pathway. In conclusion, our study indicates that gastrodin can suppress neuronal ferroptosis probably through an exosome-mediated mechanism involving the miR-455\u20135p\/ACSL4 pathway, thereby exerting neuroprotective effects after ischemic injury. In addition, exosomal delivery represents a promising strategy to treat stroke.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1882367","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T10:27:12Z","timestamp":1790850432000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Gastrodin inhibits neuronal ferroptosis by regulating mir-455\u20135p\/ACSL4 pathway after stroke via exosome"],"prefix":"10.3389","volume":"17","author":[{"given":"Yinan","family":"Nan","sequence":"first","affiliation":[{"name":"China-Japan Friendship Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhao","family":"Zhu","sequence":"additional","affiliation":[{"name":"ZiBo Hospital of Traditional Chinese Medicine","place":["Zibo, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoqing","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Tiantan Hospital Affiliated to Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1262","DOI":"10.1016\/j.cell.2019.03.032","article-title":"Selenium drives a transcriptional adaptive program to block ferroptosis and treat stroke","volume":"177","author":"Alim","year":"2019","journal-title":"Cell"},{"key":"B2","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1038\/nbt.1807","article-title":"Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes","volume":"29","author":"Alvarez-Erviti","year":"2011","journal-title":"Nat. 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