{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T02:51:57Z","timestamp":1790391117398,"version":"4.1.0"},"reference-count":43,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T00:00:00Z","timestamp":1686268800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Ischemic stroke (IS) is a detrimental neurological disease with limited treatment options. Astragaloside IV (As\u2010IV) was a promising bioactive constituent in the treatment of IS. However, the functional mechanism remains unclear. Here, IS cell and mouse models were established by oxygen glucose deprivation\/re\u2010oxygenation (OGD\/R) and middle cerebral artery occlusion (MCAO). Quantitative reverse transcription PCR (RT\u2013qPCR), Western blotting, or Immunofluorescence staining measured related gene and protein expression of cells or mice brain tissues, and the results revealed altered expression of acyl\u2010CoA synthetase long\u2010chain family member 4 (Acsl4), fat mass and obesity\u2010associated (Fto), and activation transcription factor 3 (Atf3) after treatment with As\u2010IV. Then, increased N<jats:sup>6<\/jats:sup>\u2010methyladenosine (m<jats:sup>6<\/jats:sup>A) levels caused OGD\/R or MCAO were reduced by As\u2010IV according to the data from methylated RNA immunoprecipitation (MeRIP)\u2010qPCR and dot blot assays. Moreover, through a series of functional experiments such as observing mitochondrial changes under transmission electron microscopy (TEM), evaluating cell viability by cell counting kit\u20108 (CCK\u20108), analyzing infract area of brain tissues by 2,3,5\u2010triphenyltetrazolium chloride (TTC) staining, measuring levels of malondialdehyde (MDA), lactate dehydrogenase (LDH), Fe<jats:sup>2+<\/jats:sup>, solute carrier family 7 member 11 (Slc7a11) and glutathione peroxidase 4 (Gpx4) and concentration of glutathione (GSH), we found that Fto knockdown, Acsl4 overexpression or Atf3 knockdown promoted the viability of OGD\/R cells, inhibited cell ferroptosis, reduced infract size, while As\u2010IV treatment or Fto overexpression reversed these changes. In mechanism, the interplays of YTH N<jats:sup>6<\/jats:sup>\u2010methyladenosine RNA\u2010binding protein 3 (Ythdf3)\/Acsl4 and Atf3\/Fto were analyzed by RNA\u2010pull down, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP) and dual\u2010luciferase reporter assay. Fto regulated the m<jats:sup>6<\/jats:sup>A levels of Acsl4. Ythdf3 bound to <jats:italic>Acsl4<\/jats:italic>, and modulated its levels through m<jats:sup>6<\/jats:sup>A modification. Atf3 bound to <jats:italic>Fto<\/jats:italic> and positively regulated its levels. Overall, As\u2010IV promoted the transcription of Fto by upregulating Atf3, resulting in decreased m<jats:sup>6<\/jats:sup>A levels of Acsl4, thus, improving neuronal injury in IS by inhibiting ferroptosis.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15871-fig-0010-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.15871","type":"journal-article","created":{"date-parts":[[2023,6,10]],"date-time":"2023-06-10T05:50:22Z","timestamp":1686376222000},"page":"328-345","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Astragaloside IV alleviates neuronal ferroptosis in ischemic stroke by regulating fat mass and obesity\u2010associated\u2014N6\u2010methyladenosine\u2014acyl\u2010CoA synthetase long\u2010chain family member 4 axis"],"prefix":"10.1111","volume":"166","author":[{"given":"Zhenglong","family":"Jin","sequence":"first","affiliation":[{"name":"Department of Neurology Affiliated Jiangmen Traditional Chinese Medicine Hospital of Ji'nan University  Jiangmen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenying","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of TCM Pediatrics Jiangmen Maternal and Child Health Hospital  Jiangmen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fu","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Neurology Affiliated Jiangmen Traditional Chinese Medicine Hospital of Ji'nan University  Jiangmen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaojun","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Spine Guangdong Provincial Hospital of Chinese Medicine  Guangzhou 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