{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T01:27:35Z","timestamp":1792114055802,"version":"4.4.0"},"reference-count":174,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:00Z","timestamp":1767744000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100018453","name":"Darmstadt University of Applied Sciences","doi-asserted-by":"publisher","award":["none"],"award-info":[{"award-number":["none"]}],"id":[{"id":"10.13039\/100018453","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Neurodegenerative diseases such as Alzheimer\u2019s disease (AD), Parkinson\u2019s disease (PD), and Huntington\u2019s 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.<\/jats:p>","DOI":"10.3390\/biom16010103","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T16:14:12Z","timestamp":1767802452000},"page":"103","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Epigenetic Dysregulation in Neurodegeneration: The Role of Histone Deacetylases and Emerging Inhibitor Strategies"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-6564-8603","authenticated-orcid":false,"given":"Yogesh","family":"Pawar","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Bharati Vidyapeeth\u2019s College of Pharmacy, CBD Belapur, Navi Mumbai 400614, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Kopranovic","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Biotechnology, University of Applied Science, 64290 Darmstadt, Germany"},{"name":"European University of Technology, European Union, 64290 Darmstadt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramaa","family":"C S","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Bharati Vidyapeeth\u2019s College of Pharmacy, CBD Belapur, Navi Mumbai 400614, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1001-3249","authenticated-orcid":false,"given":"Franz-Josef","family":"Meyer-Almes","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Biotechnology, University of Applied Science, 64290 Darmstadt, Germany"},{"name":"European University of Technology, European Union, 64290 Darmstadt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lima, A.A., Mridha, M.F., Das, S.C., Kabir, M.M., Islam, R., and Watanobe, Y. 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