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This study investigated the involvement of the N6\u2010methyladenosine (m6A) demethylase FTO in the pathogenesis of CIRI and explored the underlying molecular mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We established a middle cerebral artery occlusion (MCAO) mouse model in\u00a0vivo and an oxygen\u2013glucose deprivation\/reperfusion (OGD\/R) model in primary astrocytes in\u00a0vitro.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      FTO expression was significantly downregulated in both the in\u00a0vivo and in\u00a0vitro CIRI models. Upregulation of FTO via plasmid transfection significantly attenuated cellular damage and enhanced astrocyte viability. At the molecular level, m6A\u2010modified transcripts were enriched in the MAPK signaling pathway during cerebral ischemia\u2013reperfusion. Notably, Heat Shock Protein Family A (Hsp70) Member 1A (\n                      <jats:italic>Hspa1a<\/jats:italic>\n                      ) was identified as a key target. The reduction in FTO expression led to increased m6A methylation levels on\n                      <jats:italic>Hspa1a<\/jats:italic>\n                      mRNA, thereby promoting its degradation. Furthermore, the cellular damage induced by FTO silencing was alleviated by\n                      <jats:italic>Hspa1a<\/jats:italic>\n                      overexpression or the silencing of Aquaporin\u20104 (AQP4).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This study demonstrates that FTO mitigates CIRI by stabilizing\n                      <jats:italic>Hspa1a<\/jats:italic>\n                      mRNA, which in turn suppresses AQP4 expression. Consequently, FTO represents a promising therapeutic target for the treatment of ischemic stroke.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cns.71011","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:19:12Z","timestamp":1785903552000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>N6<\/scp>\n                    \u2010Methyladenosine Demethylase\n                    <scp>FTO<\/scp>\n                    Mitigates Cerebral Ischemia\u2013Reperfusion Injury by Suppressing\n                    <scp>AQP4<\/scp>\n                    Expression"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0399-6216","authenticated-orcid":false,"given":"Wei","family":"Chen","sequence":"first","affiliation":[{"name":"Provincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Department of General Surgery Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luyuan","family":"Cao","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences and Forensic Medicine Hangzhou Medical College  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxiao","family":"Zheng","sequence":"additional","affiliation":[{"name":"Cancer Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyuan","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Tongde Hospital of Zhejiang Province, 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