{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:28:44Z","timestamp":1786969724308,"version":"build-2736575974"},"reference-count":175,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,16]],"date-time":"2026-08-16T00:00:00Z","timestamp":1786838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Major depressive disorder (MDD) is a heterogeneous psychiatric disorder characterized by impaired mood, neuroplasticity, neuroinflammation, and dysregulated stress response systems. Chronic stress can induce epigenetic changes leading to depression. Evidence suggests that histone acetylation and deacetylation are epigenetic processes involved in changes in gene expression. Histone deacetylases (HDACs) modulate chromatin structure and transcription, and their dysregulation is associated with stress susceptibility, decreased brain-derived neurotrophic factor (BDNF) signaling, impaired synaptic plasticity, and inflammatory activation. HDAC isoforms HDAC3 and HDAC6 have emerged as epigenetic regulators in stress-induced depression. HDAC3 is a transcriptional regulator involved in neuroplasticity-related gene expression, inflammatory signaling, and glucocorticoid receptor-mediated stress responses. In contrast, HDAC6 is cytoplasmic and regulates non-histone substrates involved in microtubule dynamics, synaptic function, protein trafficking, and the regulation of the hypothalamic\u2013pituitary\u2013adrenal axis (HPA axis). Preclinical studies show that HDAC3 or HDAC6 inhibition can exert antidepressant-like effects by promoting neuroplasticity, reducing neuroinflammation, and restoring stress-related signaling. Dual targeting is an interesting therapeutic approach because both regulate complementary mechanisms. However, clinical translation is limited by poor blood\u2013brain barrier penetration, systemic toxicity, insufficient isoform selectivity, and a lack of clinical evidence. This review summarizes the roles and mechanisms of HDAC3 and HDAC6, the rationale for dual targeting, translational limitations, and future therapeutic perspectives.<\/jats:p>","DOI":"10.3390\/ijms27167313","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:01:26Z","timestamp":1786968086000},"page":"7313","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Epigenetic Control of Stress-Induced Depression: Emerging Roles of HDAC3 and HDAC6"],"prefix":"10.3390","volume":"27","author":[{"given":"Arathy S.","family":"Mohan","sequence":"first","affiliation":[{"name":"Department of Pharmacology, SRM College of Pharmacy, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu 603203, Tamil Nadu, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6149-2761","authenticated-orcid":false,"given":"Narayanan","family":"Jayasankar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, SRM College of Pharmacy, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu 603203, Tamil Nadu, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8467-2183","authenticated-orcid":false,"given":"Vivekanand Ankush","family":"Kashid","sequence":"additional","affiliation":[{"name":"MABD Institute of Pharmaceutical Education and Research, Babhulgaon, Yeola, Nashik 423401, Maharashtra, India"},{"name":"Centre for Research Impact and Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8442-0349","authenticated-orcid":false,"given":"Ravish J.","family":"Patel","sequence":"additional","affiliation":[{"name":"Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, CHARUSAT Campus, Anand 388421, Gujarat, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8242-4541","authenticated-orcid":false,"given":"Bhupendra","family":"Prajapati","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Parul Institute of Pharmacy, Faculty of Pharmacy, Parul University, Waghodia, Vadodara 391760, Gujarat, India"},{"name":"Department of Industrial Pharmacy, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,16]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2026, August 13). 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