histone deacetylase 1

Overview

Histone deacetylase 1 (HDAC1) is a member of the class I histone deacetylase family and a nuclear enzyme that removes acetyl groups from lysine residues on histone and non-histone proteins. By promoting chromatin condensation and altering transcriptional accessibility, HDAC1 helps regulate gene expression programs involved in cell proliferation, differentiation, stress responses, inflammation, and metabolic control. It is therefore an important epigenetic regulator in both normal physiology and disease.

In biomedical research, HDAC1 is frequently studied as a therapeutic target because altered HDAC1 activity or expression can contribute to inflammatory signaling, endothelial dysfunction, metabolic disease, and other pathological states. It is also used as a reference selectivity target in drug discovery, particularly in the development of HDAC inhibitors designed to distinguish HDAC1 from related isoforms such as HDAC6.

Focus of Latest Publications

Recent publications have focused on histone deacetylase 1 (HDAC1) as a regulator of disease-associated transcriptional programs, particularly in cancer, vascular dysfunction, and inflammatory conditions. In pancreatic ductal adenocarcinoma, HDAC1/2 were identified as critical regulators of the DNA damage response by controlling the genomic distribution of H3K27ac and maintaining BRD4 and RNA polymerase II occupancy at DNA damage response gene promoters. Pharmacologic HDAC inhibition with entinostat shifted H3K27ac toward intergenic regions, reduced promoter-associated transcriptional machinery, suppressed DNA damage response gene expression, and increased sensitivity of pancreatic tumors to DNA-damaging and DDR-targeting agents. The same study also developed bottlebrush prodrug nanoparticles for tumor-selective entinostat delivery, aiming to improve efficacy while reducing systemic toxicity.

Several studies examined HDAC1 in inflammatory and metabolic disease contexts. In diabetes-associated endothelial dysfunction, intermittent high glucose was associated with increased HDAC1 expression, reduced H4K5 acetylation, and repression of the KLF2-eNOS axis in endothelial cells and diabetic rat glomeruli. Pharmacological inhibition of HDAC1 with pyroxamide or HDAC1 siRNA restored H4K5 acetylation, reinstated KLF2 and eNOS expression, and reduced ICAM1-associated endothelial activation and THP1 cell binding. Another study linked HDAC1 to the miR-34a-5p/HDAC1 axis in sepsis, evaluating lncRNA PAX8-AS1 as a diagnostic and prognostic biomarker and exploring its regulatory role in inflammatory responses. In metabolic dysfunction-associated steatohepatitis, HLWDD was reported to attenuate hepatic inflammation and lipogenesis via inhibition of the NF-κB/HDAC1/SREBP-1c axis.

HDAC1 has also been a target in medicinal chemistry efforts to develop selective epigenetic modulators. One study synthesized indole-based derivatives derived from vorinostat and entinostat and evaluated them against HDAC1 and HDAC6, identifying benzamide compounds with preferential HDAC1 inhibition and hydroxamate compounds with stronger HDAC6 preference. These compounds showed antiproliferative activity in cancer cell and NCI-60 screening assays, supporting HDAC1/6 inhibition as a strategy for cancer therapy. A separate computational study of vernomenin from Vernonia amygdalina included HDAC1 among fever-related targets identified by network pharmacology and docking, although the strongest predicted binding was to sirtuin 1 rather than HDAC1.

Overall, the recent literature portrays HDAC1 as a transcriptional and epigenetic regulator implicated in DNA damage responses, endothelial inflammation, and inflammatory-metabolic signaling, while also remaining an important target for inhibitor design. Across these studies, HDAC1-directed interventions were associated with altered histone acetylation, changes in promoter occupancy by transcriptional machinery, and downstream effects on genes such as KLF2, eNOS, BRD4-associated DDR genes, and SREBP-1c.

Key Publications

NEWJun HDAC inhibition sensitizes pancreatic tumors to DNA damage by global redistribution of the transcriptional machinery. (Proceedings of the National Academy of Sciences of the United States of America, 2026, PMID 42348617): "HDAC1/2 direct the genomic distribution of H3K27ac, ensuring sufficient BRD4 and RNA polymerase II (Pol II) occupancy at DDR gene promoters."
NEWJun Huanglian Wendan Decoction attenuates hepatic inflammation and lipogenesis via inhibition of the NF-κB/HDAC1/SREBP-1c axis. (Journal of ethnopharmacology, 2026, PMID 42276391): "Huanglian Wendan Decoction attenuates hepatic inflammation and lipogenesis via inhibition of the NF-κB/HDAC1/SREBP-1c axis."
Jun Thiazole-Linked N-Hydroxypropanamide Derivatives: Selective HDAC6 Inhibitors with Therapeutic Potential for Neurodegenerative Diseases. (Journal of medicinal chemistry, 2026, PMID 42241502): "N-Hydroxy-3-(2-(6-methoxynaphthalen-2-yl)thiazol-4-yl)propanamide (5h) was identified as a potent HDAC6 inhibitor (IC50 = 25.56 nM) with ∼500-fold selectivity over HDAC1."
May Histone H4K5 deacetylation by enhanced HDAC1 expression drives endothelial inflammation in diabetes through repression of the KLF2-eNOS axis. (Human cell, 2026, PMID 42207449): "Targeting HDAC1 thus presents a promising therapeutic approach for mitigating vascular complications associated with diabetes."
May Clinical value of LncRNA PAX8-AS1 as a biomarker for sepsis diagnosis and prognosis and its regulatory mechanism via the miR-34a-5p/HDAC1 axis. (Inflammation research : official journal of the European Histamine Research Society ... [et al.], 2026, PMID 42154028): "...its regulatory mechanism via the miR-34a-5p/HDAC1 axis."
Mar Towards the discovery of potent epigenetic modulators: Design, synthesis, biological evaluation, and SAR investigation of novel indole-based derivatives targeting HDAC1 and HDAC6. (Bioorganic chemistry, 2026, PMID 41880788): "The synthesized compounds were evaluated against HDAC1 and HDAC6 isoforms, revealing that all the hydroxamate derivatives (15a-c, 16a, 16b, 17, and 18) displayed potent HDAC1/6 inhibitory activity with preferential inhibition of HDAC6."
Apr Computational profiling of vernomenin from Vernonia amygdalina via network pharmacology and molecular modeling: a preliminary assessment for fever targeting. (Journal of molecular graphics & modelling, 2026, PMID 41691789): "Network pharmacology was employed to screen bioactive compounds and identify fever-related targets (SIRT1, TP53, HDAC1),"