{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:31:50Z","timestamp":1791361910450,"version":"4.3.1"},"reference-count":52,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T00:00:00Z","timestamp":1740960000000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>Reprogramming of glycometabolism plays a crucial role in the pathogenesis of cerebral ischemia\u2013reperfusion injury (CIRI). Sestrin2 (SESN2), a sensor upstream of the mTORC1, is closely related to glycometabolism. However, the effect and mechanism of SESN2 in CIRI are unclear. The goal of this research was to explore the effect of SESN2 on CIRI and its potential mechanisms related to glycometabolism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Lentiviral vectors carrying SESN2 shRNA (Lenti\u2010SESN2) or negative NC virus (Lenti\u2010GFP) or rapamycin (mTOR inhibitor) were employed in the oxygen\u2013glucose deprivation\/reoxygenation (OGD\/R) model and in the middle cerebral artery occlusion (MCAO) mice. In all, 3\u2009days after I\/R, neurological deficit scores and infarct size were assessed. The glycolysis and SESN2 levels were determined by RT\u2010qPCR, Western blots, and immunofluorescence staining. Lactate levels were detected by a lactate assay kit, and the expression of the p\u2010mTOR\/HIF\u20101\u03b1 signaling pathway was measured by immunofluorescence staining and protein blotting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Local SESN2 deficiency in brain tissue increased the infarct size and reduced neurological scores 3\u2009days after I\/R. Moreover, the results showed that local SESN2 deficiency in brain tissue increased the expression of glycolysis\u2010related proteins, including HK2, PFKM, PKM1, PKM2, and GLUT1. The lactate assay kit showed that local SESN2 deficiency in brain tissue increased lactate levels. In addition, local SESN2 deficiency in brain tissue improved the expression of the p\u2010mTOR\/HIF\u20101\u03b1 pathway. However, rapamycin (RAP) treatment reversed these results, suggesting that SESN2 may influence IS injury by regulating glycometabolism via p\u2010mTOR\/HIF\u20101\u03b1 pathway regulation. SESN2 knockdown in BV2 cells improved the glycolysis levels and the expression of the mTOR\/HIF\u20101\u03b1 pathway in the OGD\/R model in\u00a0vitro, but RAP treatment can also reverse these results.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Knockdown of SESN2 in MCAO mice increased the expression of the p\u2010mTOR\/HIF\u20101\u03b1 pathway, which increased glycolysis and lactate levels and, in turn, affected IS injury.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/cns.70314","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T22:47:34Z","timestamp":1741733254000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Knockdown of\n                    <scp>SESN2<\/scp>\n                    Exacerbates Cerebral Ischemia\u2013Reperfusion Injury Through Enhancing Glycolysis via the\n                    <scp>mTOR<\/scp>\n                    \/\n                    <scp>HIF<\/scp>\n                    \u20101\u03b1 Pathway"],"prefix":"10.1111","volume":"31","author":[{"given":"Zhihui","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Neurosurgery Renmin Hospital of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingao","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Renmin Hospital of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonggang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Renmin Hospital of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Renmin Hospital of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Rohul","family":"Amin","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Renmin Hospital of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6989-4076","authenticated-orcid":false,"given":"Ran","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Renmin Hospital of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1928-8772","authenticated-orcid":false,"given":"Lijuan","family":"Gu","sequence":"additional","affiliation":[{"name":"Central Laboratory Renmin Hospital of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6983-8547","authenticated-orcid":false,"given":"Xiaoxing","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Renmin Hospital of Wuhan University  Wuhan 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