REVIEW article
Front. Aging Neurosci.
Sec. Alzheimer's Disease and Related Dementias
Volume 17 - 2025 | doi: 10.3389/fnagi.2025.1647967
Naringenin as a neurotherapeutic agent in Alzheimer's disease: Epigenetic signatures, gut microbiota alterations, and molecular neuroprotection
Provisionally accepted
- Department of Gastroenterology, Wenzhou People’s Hospital, Wenzhou, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Alzheimer's disease (AD) remains a major neurodegenerative disorder characterized by progressive cognitive decline, amyloid-β (Aβ) aggregation, tau pathology, oxidative stress, and chronic neuroinflammation. In recent years, the dietary flavonoid naringenin, abundant in citrus fruits, has gained attention as a multi-target neuroprotective agent with potential application in AD therapy. Preclinical studies demonstrate that naringenin exhibits robust antioxidant activity, notably through activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway, which reduces ROS and preserves mitochondrial integrity. Furthermore, naringenin upregulates AMPK-mediated autophagy, aiding in the clearance of toxic Aβ peptides and promoting neuronal survival. Inflammatory cascades are significantly downregulated following naringenin treatment. Additionally, naringenin modulates estrogen receptor and PI3K/Akt signaling, contributing to enhanced neuronal viability and reduced apoptosis. Notably, its ability to inhibit acetylcholinesterase suggests promise for restoring cholinergic neurotransmission. Despite these benefits, naringenin's poor solubility and limited oral bioavailability hinder clinical translation. To address these challenges, advanced nanocarrierbased delivery systems have been engineered to facilitate blood-brain barrier penetration and sustained brain targeting, markedly improving cognitive outcomes in animal models. Safety profiles in rodents indicate low toxicity at therapeutic doses, reinforcing its viability as a candidate compound. This review highlights the multifaceted mechanisms and delivery strategies of naringenin in AD, and underscores the need for well-designed clinical trials to confirm its efficacy and safety in humans.
Keywords: Naringenin, Alzheimer's disease, epigenetic, Gut Microbiota, molecular neuroprotection
Received: 16 Jun 2025; Accepted: 24 Jul 2025.
Copyright: © 2025 Ke. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Long Ke, Department of Gastroenterology, Wenzhou People’s Hospital, Wenzhou, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.