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Epigenetic Dysregulation in Neurodegeneration: The Role of Histone Deacetylases and Emerging Inhibitor Strategies.

Pawar Y, Kopranovic A, C S R, Meyer-Almes FJ
Biomolecules 2026
Open on PubMed

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are characterized by complex pathologies with progressive neurodegeneration, protein misfolding, oxidative stress, and persistent inflammation. Recent findings indicate the pivotal involvement of epigenetic disruption, particularly aberrant histone deacetylase (HDAC) activity, in disease initiation and progression. In the current review, we systematically discuss the mechanistic function of HDACs across all classes (I, IIa, IIb, III, and IV) in neurodegenerative disease mechanisms, such as their involvement in the modulation of gene expression, mitochondrial function, proteostasis, and neuronal survival. We discuss the therapeutic potential, as well as limitations, of HDAC inhibitors (HDACis), such as pan-inhibitors and isoenzyme-selective inhibitors, and new multi-target-directed ligands with HDAC inhibition combined with acetylcholinesterase modulation, PDE modulation, MAO-B inhibition, or NMDAR modulation. Particular emphasis is placed on the development of HDAC6-selective inhibitors with enhanced brain permeability and reduced toxicity, which have shown promising preclinical efficacy in ameliorating hallmark pathologies of AD, PD, and HD. In addition, s-triazine-based scaffolds have recently emerged as promising chemotypes in HDAC inhibitor design, offering favorable pharmacokinetic profiles, metabolic stability, and the potential for dual-target modulation relevant to neurodegeneration. The review also explores the future of HDAC-targeted therapies, including PROTAC degraders, dual-inhibitor scaffolds, and sustainable, BBB-penetrant molecules. Collectively, this review underscores the importance of HDAC modulation as a multifaceted strategy in the treatment of neurodegenerative diseases and highlights the need for continued innovation in epigenetic drug design.

19 Figures Extracted
Figure 1
Figure 1 PMC
Epigenetic mechanisms regulating chromatin structure and gene expression.
Figure 2
Figure 2 PMC
HDAC-driven epigenetic modulation in Alzheimer’s disease: impacts on protein aggregation, synaptic plasticity, and memory decline [ 58 ].
Figure 3
Figure 3 PMC
Structures of chemotherapeutic agents studied as HDAC inhibitors.
Figure 4
Figure 4 PMC
Evolution of scaffold modification showing the influence of hydroxamic acid derivatives on HDAC inhibition potency.
Figure 5
Figure 5 PMC
Synergistic neuroprotection and cognitive enhancement via dual HDAC and PDE9/PDE5 inhibition.
Figure 6
Figure 6 PMC
Mechanistic pathways of dual HDAC and NMDAR inhibition for neuroprotective therapy in Alzheimer’s disease.
Figure 7
Figure 7 PMC
Structure–activity relationship (SAR) of acridine based analogs on HDAC inhibition potency.
Figure 8
Figure 8 PMC
A multifunctional therapeutic approach targeting epigenetic, cholinergic, and amyloid pathways in Alzheimer’s disease.
Figure 9
Figure 9 PMC
Structure–activity relationship (SAR) showing the effect of various substituents on HDAC inhibition and anti-Alzheimer’s potential of MTDLs.
Figure 10
Figure 10 PMC
HDAC6-mediated pathways in Parkinson’s disease: intersections between autophagy, α-synuclein aggregation, and immune activation [ 58 ]. Solid arrows i...
Figure 11
Figure 11 PMC
Progressive stages of Huntington’s disease along the clinical timeline.
Figure 12
Figure 12 PMC
Role of HDAC isoenzyme in Huntington’s disease pathogenesis: crosstalk between transcriptional dysregulation and synaptic impairment [ 58 ].
Figure 13
Figure 13 PMC
Structure–activity relationship of class IIa histone deacetylase inhibitors highlighting the influence of heterocyclic modifications in Huntington’s d...
Figure 14
Figure 14 PMC
Dual epigenetic and RIPK1-targeting compound in Huntington’s disease treatment.
Figure 15
Figure 15 PMC
HDAC6 inhibitors in Huntington’s disease treatment.
Figure 16
Figure 16 PMC
SAR of S-triazine-containing compounds.
Figure 17
Figure 17 PMC
S-Triazine derivatives showing histone deacetylase (HDAC) inhibition.
Figure 18
Figure 18 PMC
Mechanistic overview of HDAC inhibitor-mediated antitumor effects in glioblastoma [ 58 ].
Figure 19
Figure 19 PMC
Structural representation of HDAC-selective inhibitors illustrating key pharmacophoric variations for glioblastoma.
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