{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T05:40:28Z","timestamp":1775108428064,"version":"3.50.1"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T00:00:00Z","timestamp":1775088000000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cerebral ischemia\u2013reperfusion injury (CIRI) remains a major cause of neurological disability and lacks effective neuroprotective interventions. Soy isoflavones (SI), phytoestrogens with antioxidant and anti-inflammatory properties, have shown neuroprotective potential. Given that ferroptosis contributes to CIRI pathogenesis and AMP-activated protein kinase (AMPK) regulates redox homeostasis, iron metabolism, and lipid peroxidation, we investigated whether SI protect against CIRI by activating AMPK and inhibiting ferroptosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Male Sprague\u2013Dawley rats subjected to middle cerebral artery occlusion (MCAO) were pretreated with SI (120 mg\/kg, gavage) for 21 days. Neurological outcomes were assessed by infarct volume (TTC), brain water content, and behavioral scoring (Longa, mNSS). Ferroptosis was evaluated via cerebral Fe\u00b2\n                      <jats:sup>+<\/jats:sup>\n                      \/total iron levels, oxidative stress indices (MDA, GSH, SOD, ROS), and protein expression of GPX4, ACSL4\/3, xCT, and ferritin (FTH\/FTMT). AMPK activation (p-AMPK\/AMPK) was determined by Western blotting. Mechanistic validation employed RSL3 (ferroptosis inducer) and compound C (AMPK inhibitor).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>SI pretreatment significantly reduced infarct size, alleviated edema, and improved neurological function. SI attenuated cerebral iron accumulation, suppressed ROS and MDA production, and enhanced GSH and SOD activities. Western blot analysis revealed downregulation of ACSL4 and upregulation of GPX4, ACSL3, xCT, and ferritin, consistent with ferroptosis suppression. The protective effects of SI were abolished by RSL3, confirming ferroptosis dependence. Furthermore, MCAO suppressed AMPK activation, which was restored by SI; inhibition of AMPK with compound C intensified ferroptotic injury and negated SI\u2019s benefits, whereas co-treatment with SI reversed these detrimental effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>SI confer neuroprotection against CIRI by activating AMPK signaling and inhibiting ferroptosis. These findings highlight the AMPK\u2013ferroptosis axis as a promising therapeutic target for ischemic stroke.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1663986","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T04:14:29Z","timestamp":1775103269000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Ferroptosis inhibition and AMPK activation: key mechanisms of soy isoflavones against cerebral injury"],"prefix":"10.3389","volume":"17","author":[{"given":"Cailian","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Emergency, The Second Affiliated Hospital of Guangxi Medical University","place":["Nanning, Guangxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiantian","family":"Luo","sequence":"additional","affiliation":[{"name":"Mental Health Center, The Second Affiliated Hospital of Guangxi Medical University","place":["Nanning, Guangxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinfeng","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation, The First People\u2019s Hospital of Nanning","place":["Nanning, Guangxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruikang","family":"Mo","sequence":"additional","affiliation":[{"name":"Department of Neurology, The First People\u2019s Hospital of Nanning","place":["Nanning, Guangxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1186\/s13049-016-0251-2","article-title":"Effect of prehospital notification on acute stroke care: a multicenter study","volume":"24","author":"Hsieh","year":"2016","journal-title":"Scand J Trauma Resusc Emerg 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