Targeting Hippocampal PTEN Suppresses Ferroptosis and Rescues Cognitive Decline in Alzheimer's Disease via Dual AKT/GSK3β/Nrf2 and AKT/STAT3 Axes.

Overview

1. 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 China
2. Department of Neurology Second Affiliated Hospital Army Medical University (Third Military Medical University) Chongqing China
3. Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province Department of Physical Education Institute of China Medical University Shenyang China
4. Laboratory 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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

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• ncbi.nlm.nih.gov/geo — NCBI; found in the text, “Databases and Bioinformatic Analysis”

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Recorded: type, language, journal, pages, dates, 6 authors, 6 keywords, 3 funders, 56 references.

Cite

This paper

Wang, D., Liu, M., Zhao, Y., Li, J., Li, W., & Yu, X. (2026). Targeting Hippocampal PTEN Suppresses Ferroptosis and Rescues Cognitive Decline in Alzheimer's Disease via Dual AKT/GSK3β/Nrf2 and AKT/STAT3 Axes. Advanced science (Weinheim, Baden-Wurttemberg, Germany), e76989. https://doi.org/10.1002/advs.76989

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