Targeting Hippocampal PTEN Suppresses Ferroptosis and Rescues Cognitive Decline in Alzheimer's Disease via Dual AKT/GSK3β/Nrf2 and AKT/STAT3 Axes
4 affiliations
- 1Key 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 China
- 2Department of Neurology Second Affiliated Hospital Army Medical University (Third Military Medical University) Chongqing China
- 3Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province Department of Physical Education Institute of China Medical University Shenyang China
- 4Laboratory of Research in Parkinson's Disease and Related Disorders Liaoning Provincial Key Laboratory of Major Neurological Diseases Health Sciences Institute of China Medical University Shenyang China
Abstract
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‐specific PTEN knockdown mediated by adeno‐associated 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‐signaling framework through which PTEN regulates GPX4 expression. PTEN reduction activates the PI3K/AKT axis, which drives GSK3β phosphorylation and facilitates nuclear translocation of nuclear factor erythroid 2‐related 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/GSK3β/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‐regulated ferroptotic pathway in AD pathogenesis and highlight PTEN as a promising therapeutic target for AD.
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BibTeX
@article{wang2026targeting,
title = {{Targeting Hippocampal PTEN Suppresses Ferroptosis and Rescues Cognitive Decline in Alzheimer's Disease via Dual AKT/GSK3β/Nrf2 and AKT/STAT3 Axes}},
author = {Da‐Wei Wang and Meng‐Meng Liu and Yu‐Chen Zhao and Jia‐Yi Li and Wen Li and Xin Yu},
journal = {Advanced Science},
year = {2026},
month = aug,
doi = {10.1002/advs.76989},
url = {https://doi.org/10.1002/advs.76989},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Targeting Hippocampal PTEN Suppresses Ferroptosis and Rescues Cognitive Decline in Alzheimer's Disease via Dual AKT/GSK3β/Nrf2 and AKT/STAT3 Axes
AU - Da‐Wei Wang
AU - Meng‐Meng Liu
AU - Yu‐Chen Zhao
AU - Jia‐Yi Li
AU - Wen Li
AU - Xin Yu
PY - 2026
DA - 2026/08/03
JO - Advanced Science
DO - 10.1002/advs.76989
UR - https://doi.org/10.1002/advs.76989
AB - 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‐specific PTEN knockdown mediated by adeno‐associated 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‐signaling framework through which PTEN regulates GPX4 expression. PTEN reduction activates the PI3K/AKT axis, which drives GSK3β phosphorylation and facilitates nuclear translocation of nuclear factor erythroid 2‐related 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/GSK3β/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‐regulated ferroptotic pathway in AD pathogenesis and highlight PTEN as a promising therapeutic target for AD.
SN - 2198-3844
ER -