Histone Deacetylase Inhibitor Research Articles

Transcriptional remodeling shapes therapeutic vulnerability to necroptosis in acute lymphoblastic leukemia.

Transcriptional remodeling shapes therapeutic vulnerability to necroptosis in acute lymphoblastic leukemia.

EFFECT OF KETOGENIC DIET ON SELECTED CARDIOMETABOLIC-RELATED DISEASES

Cardiometabolic diseases (CMDs) are a group of metabolic abnormalities that increase the risk of diseases such as type 2 diabetes, cardiovascular diseases, insulin resistance, non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and abdominal obesity. The study of CMDs’ comorbidity is an emerging field. In the quest to reduce the cost and side effects of drugs, fasting therapies like ketogenic diet (KD) have been proposed for treating seizure disorders, cancer, and chronic diseases. Recently, it has been reported to improve the quality of life of patients with cardiometabolic-related diseases. KD is a very low carbohydrate, high protein, very high-fat diet which induces ketogenesis, eliciting molecular signals. Intake of KD produces inhibition of histone deacetylase and 3-hydroxy-3-methyl glutaryl coA (HMG-CoA) reductase. It also increases the particulate size of low density lipoprotein cholesterol (LDL-C), lipolysis, HMG-CoA synthase 2, cataplerotic activity and high-density lipoprotein, and sirtuins production, which results in improved health status for patients with NAFLD, diabetes, and cardiovascular diseases when KD is consumed for a minimum of two weeks. There are usually mild side effects that are experienced with this therapy but these can be overcome after four (4) weeks of continuous intake of KD and with certain interventions like vitamins, minerals and calcium. There is, therefore, a need to explore ways of incorporating KD into the clinical management and treatment of cardiometabolic diseases globally.

SSRP1/SLC3A2 Axis in Arginine Transport: A New Target for Overcoming Immune Evasion and Tumor Progression in Peripheral T-Cell Lymphoma.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T-cell malignancies with poor prognosis. Therefore, improved therapies are urgently required to improve patient outcomes. In this study, metabolic inhibitor drug screening reveals that quinacrine elicits excellent antitumor activity both in vitro and in vivo by downregulating intracellular arginine levels in PTCL. Single-cell transcriptomic analyses reveal aberrant arginine metabolism in patients with PTCL, characterized by excessive solute carrier family 3 member 2 (SLC3A2) mediated arginine uptake preferentially in tumor cells. High SLC3A2 expression predicts poor outcomes in PTCL, as SLC3A2-mediated arginine uptake promotes the malignant behaviors of tumor cells and induces tumor immune escape, thereby fueling tumor progression. Mechanistically, high arginine levels induce global metabolic changes, including enhanced oxidative phosphorylation by promoting nascent RNA synthesis. This work identifies structure-specific recognition protein 1 (SSRP1), which upregulates SLC3A2, as a co-transcription factor with JUNB. Quinacrine disrupts SLC3A2-mediated arginine transport by targeting SSRP1. Combining quinacrine with histone deacetylase inhibitors is a promising therapeutic strategy for PTCL.

Serendipitous and Systematic Chemoproteomic Discovery of MBLAC2, HINT1, and NME1-4 Inhibitors from Histone Deacetylase-Targeting Pharmacophores.

Metalloenzyme inhibitors often incorporate a hydroxamic acid moiety to bind the bivalent metal ion cofactor within the enzyme's active site. Recently, inhibitors of Zn2+-dependent histone deacetylases (HDACs), including clinically advanced drugs, have been identified as potent inhibitors of the metalloenzyme MBLAC2. However, selective chemical probes for MBLAC2, which are essential for studying its inhibitory effects, have not yet been reported. To discover highly selective MBLAC2 inhibitors, we conducted chemoproteomic target deconvolution and selectivity profiling of a library of hydroxamic acid-type molecules and other metal-chelating compounds. This screen revealed MBLAC2 as a frequent off-target of supposedly selective HDAC inhibitors, including the HDAC6 inhibitor SW-100. Profiling a focused library of SW-100-related phenylhydroxamic acids led to identifying two compounds, KV-65 and KV-79, which exhibit nanomolar binding affinity for MBLAC2 and over 60-fold selectivity compared to HDACs. Interestingly, some phenylhydroxamic acids were found to bind additional off-targets. We identified KV-30 as the first drug-like inhibitor of the histidine triad nucleotide-binding protein HINT1 and confirmed its mode of inhibition through a cocrystal structure analysis. Furthermore, we report the discovery of the first inhibitors for the undrugged nucleoside diphosphate kinases NME1, NME2, NME3, and NME4. Overall, this study maps the target and off-target landscape of 53 metalloenzyme inhibitors, providing the first selective MBLAC2 inhibitors. Additionally, the discovery of pharmacophores for NME1-4 and HINT1 establishes a foundation for the future design of potent and selective inhibitors for these targets.

Inhibition of histone deacetylase 6 activity mitigates neurological impairment and post-hemorrhagic hydrocephalus after intraventricular hemorrhage by modulating pyroptosis and autophagy pathways

BackgroundPosthemorrhagic hydrocephalus (PHH) is a frequent and significant complication that impacts the prognosis of patients suffering from intraventricular hemorrhage (IVH). However, the underlying mechanism is uncertain. Neuronal pyroptosis is characterized by neuronal lysis and destruction, along with the release of inflammatory factors. Autophagy is known to inhibit inflammation, and histone deacetylase-6 (HDAC6) is implicated in the regulation of both autophagy and the NLRP3 inflammasome. However, the role of these proteins in the regulation of neuronal pyroptosis in an IVH model has not been determined.MethodsIn this study, an IVH mouse (6–8 weeks) model was generated via the intracerebroventricular administration of autologous blood at a volume of 40 µL/animal. After the surgical operation, we monitored the mice at various time points, assessing ventricle size via MRI. Additionally, during both the acute (3 days) and chronic (28 days) phases post-surgery, we examined neuronal cell damage and ventricular cilia, as well as neurological function, using HE staining, Nissl staining, scanning electron microscopy, and behavioral experiments such as neurological function scoring and water maze tests. Finally, we detected activation of the pyroptosis and autophagy pathway through western blotting and immunofluorescence staining.ResultsAutophagy induction attenuated cerebral neuronal pyroptosis caused by acute-phase autologous blood injection. HDAC6 was implicated in regulating pyroptosis in the acute phase IVH through its influence on the transcription of nuclear factor kappa-B (NF-κB). Furthermore, HDAC6 regulates excessive autophagic activation in neurons in the chronic phase of IVH. Treatment with ricolinostat improved neurological deficits and ventricular damage during the acute phase of IVH. Moreover, it alleviated mood, memory, and learning deficits in the chronic phase of IVH while also improving PHH.ConclusionsEnhanced autophagy attenuates activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and inhibits neuronal pyroptosis in the acute phase of IVH. HDAC6 plays an important role in regulating the interaction between autophagy and pyroptosis. Ricolinostat treatment significantly attenuated the upregulation of inflammatory factors and neurological impairments induced by pyroptosis in the acute phase of IVH. In addition, ricolinostat effectively reduced excessive autophagy and apoptosis in neurons in the chronic phase and attenuated the formation of PHH.

Role of histone deacetylases and sirtuins in the ischaemic stroke: a systematic review and meta-analysis of animal studies.

Treatment of ischaemic stroke requires exploration of novel neuroprotective strategies owing to the constraints of thrombolytic therapy. Recent research implies that modulation of histone deacetylases (HDAC) or sirtuins (SIRT) could be beneficial in achieving this goal. This systematic review and meta-analysis evaluates the effectiveness of HDAC/SIRT enzyme modulation in treating acute ischaemic stroke. It includes relevant studies but excludes human and in vitro research and non-primary studies. An electronic search was conducted across databases PubMed, Web of Science and Scopus until 20 March 2025. The methodological quality was assessed using a modified SYRCLE risk of bias tool. Infarct volume and neurological responses were extracted as key outcomes, and a random-effects meta-analysis of infarct volume was conducted for studies directly targeting HDAC/SIRT enzymes. A review of 71 studies involving over 1600 animals focused on ischaemic stroke treatments, predominantly using male rodents in a transient middle cerebral artery occlusion model. Most treatments were administered intraperitoneally, starting from the inception of ischaemia until 5 days afterwards. Non-selective HDAC inhibitors and SIRT1 modulators were targeted most frequently. The meta-analysis on infarct volume with 95% CI showed an overall effect estimate of -1.529 and suggested that non-selective HDAC inhibitors exhibit the most promise in reducing infarct size. Additionally, agonists of SIRT3/7, SIRT6, SIRT1 and HDAC1, along with inhibitors of SIRT5, HDAC6 and HDAC3, may play a significant role in the treatment of ischaemic stroke. Importantly, neuroprotective treatments have been found to be most effective in reducing infarct volume when administered within 24 hours following ischaemia. This study highlights the most promising neuroprotective trials for ischaemic stroke by focusing on infarct volume as a key outcome. However, relying exclusively on infarct volume may not fully capture the effectiveness of these treatments.

Epigenetic regulation by ketone bodies in cardiac diseases and repair.

Ketone bodies, particularly β-hydroxybutyrate (BHB), play an important role in the epigenetic regulation of gene expression in cardiac tissues, impacting both cardiac health and disease. This review explores the multifaceted influence of ketone bodies on epigenetic mechanisms, including histone acetylation, DNA methylation, ubiquitination, sirtuins activation, and RNA modulation. By acting as endogenous histone deacetylase inhibitors, ketone bodies enhance histone acetylation, thereby promoting the expression of genes involved in antioxidant defenses, anti-inflammatory responses, and metabolic regulation. Furthermore, BHB affects DNA methylation patterns by altering the availability of key metabolites such as S-adenosylmethionine. Ketogenic diet, which elevates BHB levels, has been shown to modulate gene expression, such as increasing FOXO3a and metallothionein 2, and improve cardiac function. This review highlights the therapeutic potential of ketone bodies in managing cardiac diseases through their epigenetic effects, underscoring the need for further research to elucidate the detailed molecular pathways and long-term impacts of these metabolic interventions.

Histone deacetylases repress the accumulation of licochalcone A by inhibiting the expression of flavonoid biosynthetic pathway-related genes in licorice (Glycyrrhiza inflata)

Histone deacetylases (HDACs) play a crucial role in regulating plant growth, stress responses, and specialized metabolism. Licorice, utilized as both food and herbal medicine for millennia, includes Glycyrrhiza inflata as one of its primary medicinal species used globally. This study investigated the regulatory function of HDAC-mediated histone deacetylation in flavonoid biosynthesis in licorice. The research identified nineteen HDACs in the G. inflata genome. Abiotic stresses and plant hormones were found to influence flavonoid compound accumulation, correlating with altered expression patterns of HDAC genes and global histone H3 acetylation (H3ac) levels. Notably, several HDAC inhibitors enhanced flavonoid accumulation in G. inflata. Subsequent RNA-seq analysis revealed that the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) activated the expression of multiple genes related to flavonoid biosynthesis. ChIP-qPCR demonstrated that SAHA treatment increased the H3ac levels of flavonoid synthesis-related genes. Furthermore, overexpression of GiHDA2b, an HDAC member, decreased, while RNAi of GiHDA2b increased, the levels of expression and H3K18 acetylation of licochalcone A (LCA) biosynthetic genes indicating its negative role in flavonoid biosynthesis. This research provides valuable insights into the regulatory roles of GiHDACs and histone deacetylation in flavonoid biosynthesis in licorice, potentially contributing to improved bioactive compound production in medicinal plants.

Histone Deacetylase Inhibitors Show a Potential Leishmanicidal Effect against Leishmania braziliensis in a Mouse Infection Model and Lead to Less Toxicity than Glucantime

Histone Deacetylase Inhibitors Show a Potential Leishmanicidal Effect against <i>Leishmania braziliensis</i> in a Mouse Infection Model and Lead to Less Toxicity than Glucantime

Venetoclax confers synthetic lethality to chidamide in preclinical models with transformed follicular lymphoma

Transformed follicular lymphoma (t-FL) is an aggressive and heterogeneous hematological malignancy with limited treatment success; the development of novel therapeutic approaches is urgently needed for patients with t-FL. Here, we conducted high-throughput screening (HTS) and in vitro experiments using t-FL cell lines and primary samples to assess the synergistic effects of the histone deacetylase inhibitor chidamide and the BCL-2 inhibitor venetoclax. In vivo efficacy was further tested in xenograft models. The combination of venetoclax and chidamide significantly inhibited cell proliferation, induced apoptosis, and arrested the cell cycle in the G0/G1 phase across multiple t-FL cell lines. Furthermore, the combined therapy effectively reduced tumor burden, extended overall survival in xenograft models, and synergistically targeted patient samples, while sparing normal PBMCs. Mechanistically, this combination disrupted mitochondrial membrane potential and modulated the Wnt signaling pathway, as evidenced by decreased protein expression levels of Wnt3a, Wnt5a/b, β-catenin, and phosphorylated GSK3β. Concurrently, the combined regimen enhanced their respective anticancer effects by inhibiting the key genes HDAC10 and BCL-xL. Taken together, venetoclax combined with chidamide presents a potent anticancer strategy in preclinical models of t-FL and merits further exploration in clinical trials to validate its effectiveness and safety for treating t-FL.

Predicting gene expression changes upon epigenomic drug treatment

Background Tumors are characterized by global changes in epigenetic modifications such as DNA methylation and histone modifications that are functionally linked to tumor progression. Accordingly, several drugs targeting the epigenome have been proposed for cancer therapy, notably, histone deacetylase inhibitors (HDACi) such as vorinostat and DNA methyltransferase inhibitors (DNMTi) such as zebularine. However, a fundamental challenge with such approaches is the lack of genomic specificity, i.e., the transcriptional changes at different genomic loci can be highly variable, thus making it difficult to predict the consequences on the global transcriptome and drug response. For instance, treatment with DNMTi may upregulate the expression of not only a tumor suppressor but also an oncogene, leading to unintended adverse effect. Methods Given the pre-treatment transcriptome and epigenomic profile of a sample, we assessed the extent of predictability of locus-specific changes in gene expression upon treatment with HDACi using machine learning. Results We found that in two cell lines (HCT116 treated with Largazole at eight doses and RH4 treated with Entinostat at 1µM) where the appropriate data (pre-treatment transcriptome and epigenome as well as post-treatment transcriptome) is available, our model distinguished the post-treatment up versus downregulated genes with high accuracy (up to ROC of 0.89). Furthermore, a model trained on one cell line is applicable to another cell line suggesting generalizability of the model. Conclusions Here we present a first assessment of the predictability of genome-wide transcriptomic changes upon treatment with HDACi. Lack of appropriate omics data from clinical trials of epigenetic drugs currently hampers the assessment of applicability of our approach in clinical setting.

Clinical efficacy and mechanistic insights of FDA-approved HDAC inhibitors in the treatment of lymphoma.

Clinical efficacy and mechanistic insights of FDA-approved HDAC inhibitors in the treatment of lymphoma.

Histone Deacetylase Inhibitors Restore the Odontogenic Differentiation Potential of Dental Pulp Stem Cells under Hyperglycemic Conditions.

Complications arising from diabetes can result in stem cell dysfunction, impairing their ability to undergo differentiation into various cellular lineages. The present study evaluated the effect of histone deacetylase inhibitors, Valproic acid and Trichostatin A, on the odontogenic differentiation potential of dental pulp stem cells under hyperglycemic conditions. Streptozotocin (STZ) induced diabetes mellitus in 12 male Wistar rats. Dental parameters were examined using micro-computed tomography. The odontogenic potential of human pulp stem cells exposed to 30 mM glucose was assessed through alkaline phosphatase assays, examination of gene expression for dentin matrix protein 1 and dentin sialoprotein using real-time PCR, and alizarin red staining for calcium deposition. Along with reduced dentin thickness and root length in diabetic rats, the results revealed a significant increase in histone deacetylase 3 and 2 gene expressions in isolated diabetic pulp tissues compared to the control groups. The gene expression of odontogenic-related markers and alkaline phosphatase activity in human cultured pulp stem cells under hyperglycemic conditions significantly decreased. Adding Valproic acid and Trichostatin A restored the odontogenic differentiation markers, including calcium deposition, gene expression of dentin sialophosphoprotein, dentin matrix protein 1, and alkaline phosphatase activity. The data suggests that hyperglycemic conditions negatively impact the odontogenic potential of pulp mesenchymal stem cells. However, histone deacetylase inhibitors improve the impaired odontogenic differentiation capacity. This study implies that histone deacetylases may represent a potential therapeutic target for enhancing the regenerative mineralization of pulp cells in diabetic patients.

The class-IIa HDAC inhibitor TMP269 promotes BMP-Smad signalling and is neuroprotective in in vitro and in vivo 6-hydroxydopamine models of Parkinson's disease.

Degeneration of midbrain nigrostriatal dopaminergic neurons is a pathological hallmark of Parkinson's disease (PD). Peripheral delivery of a compound(s) to arrest or slow this dopaminergic degeneration is a key therapeutic goal. Pan-inhibitors of histone deacetylase (HDAC) enzymes, key epigenetic regulators, have shown therapeutic promise in PD models. However as there are several classes of HDACs (ClassI-IV), class-specific inhibition will be important to ensure target specificity. Here we examine the neuroprotective potential of the Class-IIa HDAC inhibitor, TMP269. We show that TMP269 protected against 6-hydroxydopamine (6-OHDA)-induced neurite injury in SH-SY5Y cells and cultured rat ventral mesencephalic dopaminergic neurons. We find that TMP269 upregulated the neurotrophic factor BMP2 and BMP-Smad dependent transcription signalling in SH-SY5Y cells, which was necessary for its neuroprotective effect against 6-OHDA-induced injury. Furthermore, peripheral continuous infusion of 0.5mg/kg of TMP269 for 7 days via a mini-osmotic pump, reduced forelimb impairments induced by striatal 6-OHDA administration. TMP269 also protected dopaminergic neurons in the substantia nigra and their striatal terminals from striatal 6-OHDA-induced neurodegeneration and prevented the 6-OHDA-induced increases in the numbers of IBA1-positive microglia in the striatum and substantia nigra in vivo. TMP269 also prevented 6-OHDA-induced decreases in BMP2, pSmad1/5 and acetylated histone 3 levels, and it reversed 6-OHDA-induced increase in nuclear HDAC5 in dopaminergic neurons in the substantia nigra. These data add to the growing body of evidence that Class-IIa specific HDAC inhibitors may be pharmacological agents of interest for peripheral delivery with the goal of neuroprotection in PD.

Twist1 Regulates the Immune Checkpoint VISTA and Promotes the Proliferation, Migration and Progression of Pancreatic Cancer Cells.

Pancreatic cancer is one of the deadliest malignant tumours worldwide. Despite the developments in the treatments of pancreatic cancer, survival rates remain at a low level, and the mechanisms underlying the aggressive course of the cancer are not fully understood. VISTA is an immune checkpoint and has recently become a significant target in cancer treatment; however, the roles of VISTA in the development of pancreatic cancer have largely remained unknown. Histone deacetylase inhibitors (HDACi) have been reported to reverse the epithelial-mesenchymal transition (EMT) and may enhance the efficacy of anti-PD-1 therapy. The PD-L1/PD-1 immune checkpoint targeted by this therapy shares structural similarity with VISTA. Moreover, combination therapy of vorinostat and anti-PD-1 has been shown to significantly reduce tumour growth by suppressing the transcription factor c-Myc. Therefore, in this study, we aim to investigate the genes that are associated with EMT and explore the potential mechanism involving Twist1, a proto-oncogene, and VISTA in pancreatic cancer. We also sought to determine the synergistic effects of an HDACi, vorinostat, in combination with Twist1-siRNA on VISTA expression in pancreatic cancer cells' viability and proliferation. Our results revealed that Twist1 blockade in combination with vorinostat in pancreatic cancer cells suppresses EMT-associated genes and the immune checkpoint VISTA compared to treatments administered alone. As a result, identifying the genes associated with EMT in pancreatic cancer and understanding the role of Twist1 in this process is a crucial step to contribute to the identification of new targets for pancreatic cancer treatment and the improvement of existing treatment strategies.

Epigenetics Modulators as Therapeutics for Neurological Disorders.

Epigenetics mechanisms play a crucial role in regulating gene expression and cellular function in the development and progression of neurological disorders. Emerging evidence suggests that dysregulation of these epigenetic processes contributes significantly to the pathogenesis of various neurological disorders, including Alzheimer's disease, Parkinson's disease, and epilepsy. Epigenetic mechanisms, including DNA methylation, histone modification, and non-coding RNAs, significantly impact neural plasticity. The use of epigenetic modulators, including DNA methyltransferase and histone deacetylase inhibitors, offers a promising strategy to correct and modify aberrant epigenetic marks, potentially restoring neurological homeostasis. This review highlights recent research findings from ongoing clinical trials and the potential benefits and challenges of epigenetic therapies for neurological disorders. We discuss the capacity of these interventions to potentially halt or reverse disease progression, their targeted nature, and their neuroprotective effects. Additionally, we address the hurdles facing the field, including issues of specificity, delivery, and long-term efficacy.

Attenuation of Cuproptosis Through Histone Deacetylase Inhibition: A Novel Strategy for Alleviating Acute Lung Injury

Attenuation of Cuproptosis Through Histone Deacetylase Inhibition: A Novel Strategy for Alleviating Acute Lung Injury

Histone deacetylase inhibiting nanoprodrugs for enhanced chemodynamic therapy through multistage downregulating glutathione.

Histone deacetylase inhibiting nanoprodrugs for enhanced chemodynamic therapy through multistage downregulating glutathione.

Epigenetic activation of PTEN by valproic acid inhibits PI3K/AKT signaling and Burkitt lymphoma cell growth.

Epigenetic activation of PTEN by valproic acid inhibits PI3K/AKT signaling and Burkitt lymphoma cell growth.

Down-regulating HDAC2-LTA4H pathway ameliorates renal ischemia-reperfusion injury.

Down-regulating HDAC2-LTA4H pathway ameliorates renal ischemia-reperfusion injury.