{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T11:47:08Z","timestamp":1785757628717,"version":"3.56.0"},"reference-count":56,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012131","name":"Department of Science and Technology of Liaoning Province","doi-asserted-by":"publisher","award":["2024JH6\/100800008"],"award-info":[{"award-number":["2024JH6\/100800008"]}],"id":[{"id":"10.13039\/501100012131","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007620","name":"Department of Education of Liaoning Province","doi-asserted-by":"publisher","award":["LJKMZ20221207"],"award-info":[{"award-number":["LJKMZ20221207"]}],"id":[{"id":"10.13039\/501100007620","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Elevated phosphatase and tensin homolog (PTEN) expression is observed in Alzheimer's disease (AD) brain, yet the precise mechanism through which PTEN contributes to AD progression remains undefined. This study provides the direct evidence that PTEN promotes neurodegeneration by driving neuronal ferroptosis. Using APP\/PS1 transgenic mice with hippocampal\u2010specific PTEN knockdown mediated by adeno\u2010associated virus (AAV), we demonstrated that downregulation of PTEN substantially ameliorates cognitive dysfunction and neuronal loss. Mechanistically, PTEN silencing upregulated glutathione peroxidase 4 (GPX4), inhibiting lipid peroxidation and ferroptosis. We identified a dual\u2010signaling framework through which PTEN regulates GPX4 expression. PTEN reduction activates the PI3K\/AKT axis, which drives GSK3\u03b2 phosphorylation and facilitates nuclear translocation of nuclear factor erythroid 2\u2010related factor 2 (Nrf2). Concurrently, PTEN knockdown induces phosphorylation and nuclear translocation of signal transducer and activator of transcription 3 (STAT3). Both Nrf2 and STAT3 act as transcriptional activators of GPX4, establishing two convergent axes: PTEN\/AKT\/GSK3\u03b2\/Nrf2\/GPX4 and PTEN\/AKT\/STAT3\/GPX4. These pathways cooperatively upregulate GPX4 expression, thereby attenuating lipid peroxidation and inhibiting ferroptosis. Importantly, PTEN knockdown restored redox homeostasis by bolstering cellular antioxidant defenses. Our findings reveal a novel PTEN\u2010regulated ferroptotic pathway in AD pathogenesis and highlight PTEN as a promising therapeutic target for AD.<\/jats:p>","DOI":"10.1002\/advs.76989","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T11:10:05Z","timestamp":1785755405000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Hippocampal PTEN Suppresses Ferroptosis and Rescues Cognitive Decline in Alzheimer's Disease via Dual AKT\/GSK3\u03b2\/Nrf2 and AKT\/STAT3 Axes"],"prefix":"10.1002","author":[{"given":"Da\u2010Wei","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory of Medical Cell Biology of Ministry of Education Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province Health Sciences Institute of China Medical University  Shenyang 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