Histone deacetylase inhibitors
Histone deacetylase inhibitors (HDAC inhibitors, or HDACi) are therapeutic agents that inhibit histone deacetylase enzymes, thereby altering the acetylation state of histones and other cellular proteins.
Histone deacetylase inhibitors (HDAC inhibitors, or HDACi) are therapeutic agents that inhibit histone deacetylase enzymes, thereby altering the acetylation state of histones and other cellular proteins. This can modify chromatin-associated gene regulation and affect processes such as cellular differentiation, proliferation, apoptosis, and treatment response. HDAC inhibitors may act broadly across several HDAC family members or be developed with greater selectivity for individual enzymes, including HDAC1, HDAC6, and HDAC11.
HDAC inhibitors are being investigated and used primarily in oncology, including hematologic malignancies and solid tumors. Recent work has examined their activity as single agents, their ability to reprogram immature or stem-like cell states, and their use in combination with chemotherapy, antibody–drug conjugates, and checkpoint inhibitors. Examples in the recent literature include chidamide, tucidinostat, entinostat, apicidin, mocetinostat, and valproic acid (VPA). Their pharmacological evaluation has included drug-likeness, lipophilicity, toxicity, proteomics, imaging, and screening approaches.
Where the papers sit
10 papers from the last 6 months study histone deacetylase inhibitors directly · updated from PubMed 26 Oct 2026
Study type 1 clinical trial · 1 observational · 3 human data · 5 preclinical
Themes 3 themes · 1 paradigm shift · 1 new direction
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Cancer Differentiation and Stemness
Cell-state control links the cluster: HDAC inhibition reprograms stem-cell fate and suppresses hemangioma vasculogenesis, while KBTBD4 mutations impair differentiation. Tucidinostat responses in relapsed/refractory PTCL are examined through the TFH phenotype. BRCA1/2-mutant lung adenocarcinoma adds tumor-microenvironment architecture rather than a shared treatment direction. The common thread is cancer differentiation and cellular context, with predictive biomarkers and mechanism-guided therapy still unresolved.
4 papers · 40%
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Histone Deacetylase Therapeutics
Histone deacetylase inhibition is being pursued both as a therapeutic mechanism and as a discovery target. HDAC11 inhibitor searches use structure-guided screening, molecular dynamics and docking, while nanatinostat anchors translational applications. Reported effects extend from p53 and histone acetylation in hepatoma to neuronal ultrastructure and hypoxia responses. HER2-positive breast cancer work shifts toward proteogenomic selection of antibody-drug-conjugate sensitization, leaving cross-tissue biomarkers unresolved.
4 papers · 40%
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Immunotherapy Resistance Biology
Immunotherapy resistance is being approached through reproducible combination testing and tumor-cell plasticity. Entinostat and pembrolizumab provide the therapeutic frame, with NRAS and CD163 marking melanoma-associated response biology. Melanoma-to-rhabdomyosarcoma plasticity suggests lineage switching as a route around immune pressure. Evidence remains early and heterogeneous, so validated synergy and predictive biomarkers are still open questions.
2 papers · 20%
HDAC inhibitors can produce therapeutic effects by redirecting cell fate rather than by direct cytotoxicity
The KBTBD4-mutant hematopoietic stem and progenitor-cell model and the infantile hemangioma stem-cell model both treat altered differentiation as the therapeutic target, rather than assuming that HDAC inhibition must primarily kill abnormal cells. In the KBTBD4 model, mocetinostat disrupted mutant KBTBD4–CoREST activity and relieved the resulting differentiation defect; in the hemangioma model, SAHA blocked pericyte differentiation, promoted adipogenic differentiation, and suppressed vasculogenesis. Together, these findings establish cell-fate control as an independently demonstrated therapeutic mechanism for HDAC inhibitors across distinct diseases and models 42576054Aug 42240910Jun.
HDAC inhibition is a neuroprotective intervention after ischemic stroke
The ischemic-stroke model treated with apicidin assigns HDAC inhibition a role outside the cancer and tumor-growth settings used by the other papers: preserving neuronal ultrastructure after reperfusion. Unlike DMOG, which offered little neuronal protection, apicidin preserved neuronal soma and improved synaptic and glial integrity, while vascular protection remained associated with HIF activation. This makes HDAC inhibition a component-specific neurovascular intervention rather than another antitumor or differentiation-directed application 42219139May.
Papers
The 10 papers from the last 6 months that study histone deacetylase inhibitors directly, newest first, by theme and by study type. Study types come from PubMed publication types and MeSH headings.
By theme
Cancer Differentiation and Stemness (4)
- Cancer-associated KBTBD4 mutations induce differentiation defects and confer a unique therapeutic vulnerability. Cancer gene therapy · 10 Aug 2026 PMID 42576054
- TFH phenotype and response to tucidinostat in relapsed/refractory PTCL: analysis of patients from a phase IIb trial. International journal of hematology · 9 Jun 2026 PMID 42262647
- HDAC inhibition reprograms stem cell fate to suppress infantile hemangioma vasculogenesis. Angiogenesis · 4 Jun 2026 PMID 42240910
- Molecular architecture of the tumor microenvironment caused by BRCA1 and BRCA2 somatic mutations in human lung adenocarcinoma. eLife · 26 May 2026 PMID 42189716
Histone Deacetylase Therapeutics (4)
- Structure-guided identification of histone deacetylase 11 inhibitors for targeted chemotherapy through long-timescale molecular dynamics simulation. Journal of molecular modeling · 16 Sept 2026 PMID 42747587
- Spatial proteogenomic profiling uncovers sensitization strategies for antibody-drug conjugate in HER2-positive breast cancer. Cell reports. Medicine · 13 Aug 2026 PMID 42594874
- Divergent neurovascular protection: Histone deacetylase inhibition preserves neuronal ultrastructure while hypoxia-inducible factor activation maintains vascular integrity after ischemic stroke. Brain research · 31 May 2026 PMID 42219139
- [Expression of Concern] Histone deacetylase inhibitors induce in human hepatoma HepG2 cells acetylation of p53 and histones in correlation with apoptotic effects. International journal of oncology · 22 May 2026 PMID 42169657
Immunotherapy Resistance Biology (2)
- Melanoma to rhabdomyosarcoma plasticity in the setting of immunotherapy. Med (New York, N.Y.) · 20 Aug 2026 PMID 42624103
- Standardized workflow enables reproducibility of drug synergism detection: Results from a multi-center in vitro ring test on complex drug combinations in pancreatic cancer models. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 1 Jun 2026 PMID 42224741
By study type
Clinical trials (1)
- TFH phenotype and response to tucidinostat in relapsed/refractory PTCL: analysis of patients from a phase IIb trial. International journal of hematology · 9 Jun 2026 PMID 42262647
Observational studies and case reports (1)
- Melanoma to rhabdomyosarcoma plasticity in the setting of immunotherapy. Med (New York, N.Y.) · 20 Aug 2026 PMID 42624103
Human data, design not indexed (3)
- Structure-guided identification of histone deacetylase 11 inhibitors for targeted chemotherapy through long-timescale molecular dynamics simulation. Journal of molecular modeling · 16 Sept 2026 PMID 42747587
- Molecular architecture of the tumor microenvironment caused by BRCA1 and BRCA2 somatic mutations in human lung adenocarcinoma. eLife · 26 May 2026 PMID 42189716
- [Expression of Concern] Histone deacetylase inhibitors induce in human hepatoma HepG2 cells acetylation of p53 and histones in correlation with apoptotic effects. International journal of oncology · 22 May 2026 PMID 42169657
Preclinical: animal, cell and lab studies (5)
- Spatial proteogenomic profiling uncovers sensitization strategies for antibody-drug conjugate in HER2-positive breast cancer. Cell reports. Medicine · 13 Aug 2026 PMID 42594874
- Cancer-associated KBTBD4 mutations induce differentiation defects and confer a unique therapeutic vulnerability. Cancer gene therapy · 10 Aug 2026 PMID 42576054
- HDAC inhibition reprograms stem cell fate to suppress infantile hemangioma vasculogenesis. Angiogenesis · 4 Jun 2026 PMID 42240910
- Standardized workflow enables reproducibility of drug synergism detection: Results from a multi-center in vitro ring test on complex drug combinations in pancreatic cancer models. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 1 Jun 2026 PMID 42224741
- Divergent neurovascular protection: Histone deacetylase inhibition preserves neuronal ultrastructure while hypoxia-inducible factor activation maintains vascular integrity after ischemic stroke. Brain research · 31 May 2026 PMID 42219139
Written from 10 PubMed abstracts, each one listed by PMID above. Published: 2026-09-18. Drafted by language models from published abstracts; not medical advice.