PERSPECTIVE article
Front. Drug Discov.
Sec. Neurological Drugs
Volume 5 - 2025 | doi: 10.3389/fddsv.2025.1662691
This article is part of the Research TopicInsights into Next-Generation Neurodegenerative TherapeuticsView all articles
Advancing Histone Deacetylase 6 (HDAC6) as a Promising Therapeutic Target for Alzheimer's Disease: From Molecular Insights to Clinical Prospects
Provisionally accepted
- 1The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- 2Massachusetts General Hospital, Boston, United States
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Alzheimer's disease (AD) is a worldwide neurodegenerative disorder and the leading cause of dementia. Despite decades of research which has improved the understanding of AD, an effective disease-modifying therapy has yet to be developed that can prevent, stop, or reverse neuropathological changes and cognitive deficits of AD. There has been keen interest in targeting the epigenetic protein histone deacetylase 6 (HDAC6) for various human conditions leveraging its pathophysiological functions. Particularly, the pathological hallmarks of AD are aging-related accumulation of β-amyloid (Aβ) plaques and tau protein-related neurofibrillary tangles. In preclinical studies, HDAC6 inhibitors may significantly improve Aβ clearance and decrease tau aggregation and genetic deficiency of HDAC6 ameliorates cognitive deficits in mouse models of AD. While some pan-HDAC inhibitors have been FDA-approved for certain clinical indications, many HDAC6 inhibitors exhibit therapeutic potentials in preclinical studies of AD, for which we prepare this article to review and discuss recent studies and offer prospectives. We envision that the field of drug discovery of HDAC6 in AD may benefit by leveraging multimodal approaches, including structural and computational biology, medicinal chemistry, neuropathology and biomarker discovery. Using these approaches, future research will be better poised to efficiently discover new and potent HDAC6-selective inhibitors with enhanced blood-brain-barrier penetration, desirable safety and anti-AD efficacy. Considering the accumulated findings of HDAC6 and the urgent need in the field of AD, we speculate that many new small molecule inhibitors of HDAC6 will move forward enabling translational and clinical evaluations as potential therapeutics of AD.
Keywords: Alzheimer's disease, Neurodegenaration, HDAC, HDAC6, Drug Discovery, translational medicine
Received: 09 Jul 2025; Accepted: 15 Aug 2025.
Copyright: © 2025 Zhang, Zhang, Wang and Zhang. 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:
Wei Zhang, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
Can Martin Zhang, Massachusetts General Hospital, Boston, United States
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