REVIEW article
Front. Pharmacol.
Sec. Neuropharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1662241
Dual GSK3β/SIRT1 Modulators for Alzheimer's: Mechanisms, Drug Discovery and Future Perspectives
Provisionally accepted
- 1University of the Western Cape, Bellville, South Africa
- 2University of Missouri, Columbia, United States
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Alzheimer's disease (AD) remains without effective disease-modifying therapies, in part due to the limited efficacy of single-target approaches. Dual modulation of glycogen synthase kinase-3β (GSK3β), a key driver of tau hyperphosphorylation and amyloid-β (Aβ) production, and sirtuin-1 (SIRT1), a neuroprotective NAD⁺-dependent deacetylase, has emerged as a promising therapeutic strategy. This review explores the mechanistic rationale for concurrently inhibiting GSK3β and activating SIRT1 to disrupt AD's pathological cascade while enhancing endogenous neuroprotective pathways. Natural compounds such as resveratrol, berberine, pterostilbene, and quercetin exhibit this dual activity and provide scaffolds for rational drug design. However, challenges related to target selectivity, blood-brain barrier penetration, and clinical translation persist. Advances in multi-target drug discovery, including pharmacophore hybridization, structure-based modelling, and cheminformatics, nanoformulation and delivery strategies offer new avenues to overcome these hurdles. A dual GSK3β/SIRT1-targeting strategy exemplifies a systems-level approach to restoring neurophysiological balance and holds potential to achieve more effective, disease-modifying outcomes in AD.
Keywords: Alzheimer's disease, GSK3β inhibition, SIRT1 activation, tau hyperphosphorylation, Dual-target drug design, polypharmacology
Received: 08 Jul 2025; Accepted: 05 Sep 2025.
Copyright: © 2025 A. I, Kapp, Joubert and Zou. 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: Erika Kapp, University of the Western Cape, Bellville, South Africa
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