RGFP966 / BioMarin - LARVOL DELTA

Targeting HDAC3 Suppresses Ferroptosis and Demyelination in White Matter Injury by Restoring PDK4-Mediated Iron Homeostasis. (PubMed, CNS Neurosci Ther) - "HDAC3 drives ferroptosis in WMI via iron metabolism and lipid peroxidation, highlighting the HDAC3-PDK4 axis as a therapeutic target."

Journal • CNS Disorders • Hematological Disorders • Solid Tumor • HDAC3 • PDK4

Inhibition of histone deacetylases 3 attenuates imiquimod-induced psoriatic dermatitis via targeting cGAS-STING signaling in keratinocytes. (PubMed, J Transl Med) - "Our findings establish HDAC3 as a pivotal mediator of psoriasis pathogenesis through the cGAS-STING pathway via mitochondrial dysfunction. The role of HDAC3 in exacerbating epidermal hyperproliferation and inflammation highlights its potential as a therapeutic target. Targeting HDAC3 in keratinocytes may offer a novel strategy for preventing and treating psoriasis by modulating epigenetic regulation, mitochondrial homeostasis, and innate immune responses."

Journal • Dermatitis • Dermatology • Immunology • Inflammation • Metabolic Disorders • Psoriasis • HDAC3

PIM1 Phosphorylates HDAC3 for IL33 Deacetylation to Exacerbate Allergic Airway Inflammation (ATS 2025) - "Additionally, asthmatic mice were treated with the PIM1 inhibitor SGI-1776 and the HDAC3 inhibitor RGFP-966... Our findings suggest that the PIM1-HDAC3-IL-33 axis in epithelial cells plays a significant role in regulating the degree of inflammation in asthma, potentially representing a novel therapeutic mechanism for allergic asthma."

Asthma • Inflammation • Respiratory Diseases • HDAC3 • IL33 • PIM1

HDAC3 inhibition mitigates acute kidney injury by alleviating RIPK1-mediated programmed necrosis. (PubMed, Front Pharmacol) - "We found HDAC3 expression was upregulated in mouse renal tubules after ischemia/reperfusion and cisplatin treatment. In addition, RIPK1 knockdown cell assay signified that RGFP966 targeted RIPK1 and inhibited RIPK1 kinase activity. In summary, these findings established the efficacy of the HDAC3 inhibitor RGFP966 in treating AKI."

Journal • Acute Kidney Injury • Cardiovascular • Fibrosis • Immunology • Inflammation • Nephrology • Renal Disease • Reperfusion Injury • HDAC3 • RIPK1

Endothelial HDAC3 drives retinal pathological angiogenesis via HK2-mediated metabolic reprogramming. (ARVO 2025) - "Methods In vitro, we subjected bovine retinal endothelial cells (BREs) treated with and without the HDAC3 inhibitor RGFP966 to oxygen-glucose deprivation and reperfusion (6h OGD/ 18 h R) to simulate hypoxia...Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand. Describe the big picture and the implications of your findings, not the study itself and the associated details."

Diabetic Retinopathy • Ophthalmology • Retinal Disorders • Retinopathy of Prematurity • HDAC3 • HK2

Crosstalk between histone acetylation and methylation: Impact on RGC neuroprotection in glaucoma (ARVO 2025) - "Rats were treated with either δ-opioid receptor agonist (SNC-121, 1 mg/kg; i.p), histone deacetylase 3 (HDAC3) inhibitors (MS-275 or RGFP966; 1 mg/kg; i.p), or DNA methylation inhibitor (Decitabine; 1-1.5 mg/kg, i.p injections) daily for 7 days...Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand. Describe the big picture and the implications of your findings, not the study itself and the associated details."

Epigenetic controller • Glaucoma • Ophthalmology • CXCL8 • DNMT1 • DNMT3A • DNMT3B • HDAC3 • IL6 • TGFB1

Xinyin tablets affect mitophagy and cardiomyocyte apoptosis to alleviate chronic heart failure by regulating histone deacetylase 3(HDAC3)-mediated PTEN induced putative kinase 1(PINK1)/Parkin signaling pathway. (PubMed, J Ethnopharmacol) - "Xinyin tablets have potential as an intervention for CHF by improving mitophagy and inhibiting cardiomyocyte apoptosis through the HDAC3-mediated PINK1/Parkin signaling pathway."

Journal • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • BAX • CASP3 • CASP9 • HDAC3 • PINK1

Histone Deacetylase Inhibitor-Induced Phenotypic Transition of Schwann Cells Into Repair Types: Implications on Repair and Myelination During Nerve Damage [WITHDRAWN] (ARO 2025) - "Schwann cells were treated in vitro with varying concentrations of Valproic Acid, Trichostatin A, RGFP966, and Romidepsin to encompass specific inhibitory effects between specific HDACs. These results suggest that HDACi treatments can induce the phenotypic transition of Schwann cells into repair types by modulating epigenetic regulation of key transcription factors. While high doses may affect cell viability, appropriate dosing of HDACi may temporarily reduce myelination but promote early-stage repair mechanisms. This warrants further in vivo exploration to optimize HDACi treatment protocols for enhancing nerve regeneration and functional recovery."

Epigenetic controller • CNS Disorders

RGFP966 inhibits palmitic acid induced VSMCs phenotypic transition by targeting ATGL. (PubMed, Biochim Biophys Acta Mol Cell Biol Lipids) - "RGFP966 has a protective effect against VSMCs phenotype transitions, potentially related to the regulation of ATGL."

Journal • Cardiovascular • HDAC3

Evaluation of the Lethal Activity and Its Mechanism of Tasquinimod in Advanced Myeloproliferative Neoplasm (MPN) in Blastic Phase (ASH 2024) - "Importantly, cotreatment with TQ (5 to 30 µM) and ruxolitinib (250 to 1000 nM), BET inhibitor OTX015 (50 to 250 nM) or pelabresib (CPI-0610) (100 to 500 nM), or BCL2/Bcl-xL inhibitor navitoclax, induced synergistic lethality in advanced MPN-BP cells, represented by delta synergy scores of >1.0 (by the ZIP method)...Co-treatment with TQ and RGFP966 (HDAC3i) induced synergistic lethality in post-MPN sAML cells...These findings demonstrate the pre-clinical efficacy of TQ and/or JAKi or BETi or with novel agents identified here in advanced MPN and MPN-AML cells. They also create the rationale to further interrogate the pre-clinical efficacy of the TQ-based combinations against cellular models of advanced MPN."

IO biomarker • Metastases • Fibrosis • Hematological Malignancies • Immunology • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • BCL2 • BCL2L1 • CALR • CCL2 • CCND1 • CD123 • CD33 • CD34 • CD99 • CDK6 • CDKN1A • CLEC12A • CXCL12 • CXCL8 • CXCR4 • HDAC3 • IL1A • IL3RA • IL6 • ITGAM • JAK2 • MPO • MYC • NLRP3 • NSD2 • S100A8 • S100A9 • TERT • TLR4 • TNFA • TP53

Efficacy of Combinations of Targeted Agents Against Dependencies in Mecom Rearranged AML Identified By Unbiased Chemical and CRISPR Screens (ASH 2024) - "Treatment of 3q26.2-r AML cell lines for 96-hours with ORY001 (LSD1i; 3-100 nM), RGFP966 (HDAC3i; 0.5-10 µM) or GNE-781 (CBP/p300i; 10-1000 nM) induced moderate, dose-dependent cell death, as determined by flow cytometry...Treatment of the luciferized 3q26.2-r PD AML242 model, engrafted in NSG mice, with mivebresib (0.5 mg/kg, daily 5x per week), dactolisib (20 mg/kg, daily 5x per week) or LCL161 (65 mg/kg, daily 5x per week) reduced AML burden and increased survival compared to vehicle-treated mice (p < 0.05)...These treatments resulted in reduction of EVI1 and c-Myc levels, associated with preclinical differentiation and apoptotic activity in the 3q26.2-r AML cell models. Further in vivo evaluation of the efficacy of BETi or LSD1i-based combinations against 3q26.2-r AML is warranted."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BRD4 • CD86 • GATA2 • HDAC3 • ITGAM • MECOM • MYC • PIK3CA • XIAP

The Two Faces of HDAC3: Neuroinflammation in Disease and Neuroprotection in Recovery. (PubMed, Epigenomics) - "Understanding HDAC3 in the healthy brain lays the necessary foundation to define and resolve its dysfunction in a disease state. This review explores the mechanisms of HDAC3 in various cell types and its involvement in disease pathology, emphasizing the potential of HDAC3 inhibition to address neuroimmune, gene expression and behavioral deficits in a range of neurodegenerative and neuropsychiatric conditions."

Journal • Review • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Depression • Hematological Disorders • Inflammation • Mental Retardation • Psychiatry • Vascular Neurology • HDAC3

Kaempferol alleviates myocardial ischemia injury by reducing oxidative stress via the HDAC3-mediated Nrf2 signaling pathway. (PubMed, J Adv Res) - "Our data show that KAE ameliorates cardiac injury by reducing oxidative stress via the HDAC3-mediated Nrf2 signaling pathway in cardiomyocytes."

Journal • Cardiovascular • Myocardial Infarction • Myocardial Ischemia • HDAC3 • NFE2L2

Therapeutic inhibition of Histone deacetylase 3 attenuates chronic EAE (ECTRIMS 2024) - "These findings not only underscore the therapeutic potential of HDAC3 inhibition in autoimmune demyelinating diseases but also shed light on a novel epigenetic mechanism driving autoimmunity and neuroinflammatory pathologies, that expands our knowledge on the pathophysiology of these diseases and may lead to the identification of novel therapeutic targets and strategies."

Epigenetic controller • IO biomarker • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis • CXCL1 • HDAC3 • IDO1 • IL10 • IL17A

Pterostilbene improves neurological dysfunction and neuroinflammation after ischaemic stroke via HDAC3/Nrf1-mediated microglial activation. (PubMed, Cell Mol Biol Lett) - "The HDAC3/Nrf1 pathway regulates the stability and function of Nrf1 in microglial activation and neuroinflammation, which may depend on the acetylation of the lysine 105 and 139 residues in Nrf1. This mechanism was first identified as a potential regulatory mechanism of PTS-based neuroprotection in our research, which may provide new insight into further translational applications of natural products such as PTS."

Journal • Cardiovascular • CNS Disorders • Inflammation • Ischemic stroke • Vascular Neurology • HDAC3 • IL1B • NRF1 • TNFA

Biohybrid hydrogel inhibiting β-klotho/HDAC3 axis for hepatocellular carcinoma treatment. (PubMed, Int J Biol Macromol) - "By introducing the HDAC3 inhibitor RGFP966, we can selectively inhibit the activation of β-Klotho...Importantly, we have successfully validated this unique phenomenon both in vivo and in vitro, providing substantial evidence for the efficacy of this hydrogel-based anti-tumor drug delivery system as a promising strategy for HCC treatment. This innovative research outcome brings new hope to the field of tumor therapy, providing a reliable theoretical foundation for future clinical applications."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • FGF21 • HDAC3

Deletion of myeloid HDAC3 promotes efferocytosis to ameliorate retinal ischemic injury. (PubMed, J Neuroinflammation) - "Finally, treatment of wild-type mice with the HDAC3 inhibitor RGFP966 ameliorated the retinal neurodegeneration and thinning caused by IR injury. Collectively, our data show that HDAC3 deletion enhances macrophage-mediated efferocytosis and protects against retinal IR injury, suggesting that inhibiting myeloid HDAC3 holds promise as a novel therapeutic strategy for preserving retinal integrity after ischemic insult."

Journal • Cardiovascular • CNS Disorders • Diabetic Retinopathy • Inflammation • Reperfusion Injury • Retinal Disorders • HDAC3

Pharmacological HDAC3 inhibition alters memory updating in young and old male mice. (PubMed, Front Mol Neurosci) - "We show that blocking HDAC3 immediately after updating with the pharmacological inhibitor RGFP966 ameliorated age-related impairments in memory updating in 18-m.o...Consistent with our hypothesis, we found that HDAC3 blockade strengthened the subthreshold update without impairing memory for the original information, enabling balanced expression of the original and updated information. Together, this research suggests that HDAC3 may contribute to age-related impairments in memory updating and may regulate the strength of a memory update in young mice, shifting the balance between the original and updated information at test."

Journal • Preclinical • HDAC3

Macrophagic HDAC3 inhibition ameliorates Dextran Sulfate Sodium induced inflammatory bowel disease through GBP5-NLRP3 pathway. (PubMed, Int J Med Sci) - "In addition, inhibition of HDAC3 with RGFP966 could also alleviate the DSS-induced tissue injury and inflammation in IBD...Lastly, conditional knockout of Hdac3 in macrophages (Hdac3 mKO) attenuated the disease severity of DSS-induced colitis. In conclusion, inhibition of HDAC3 in macrophages could ameliorate the disease severity and inflammatory response in colitis by regulating GBP5-NLRP3 axis, identifying a new therapeutic avenue for the treatment of colitis."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • CX3CR1 • GBP5 • HDAC3 • IFNG • NLRP3

Hdac3-deficiency increases senescence-associated distention of satellite DNA and telomere-associated foci in osteoprogenitor cells. (PubMed, J Bone Miner Res) - "Senolytics reduced viable cell numbers in Hdac3 CKOOsx BMSC cultures. These data demonstrate that depletion of Hdac3 in osteochondral progenitor cells triggers LD formation and early events in cellular senescence in Runx2+ BMSCs through mutually exclusive mechanisms."

Journal • Obesity • Osteoporosis • HDAC3 • RUNX2

Histone deacetylase-3 regulates the expression of the amyloid precursor protein and its inhibition promotes neuroregenerative pathways in Alzheimer's disease models. (PubMed, FASEB J) - "For this purpose, N2a mouse neuroblastoma cells as well as organotypic brain cultures (OBCSs) of 5XFAD and wild-type mice were incubated with various concentrations of the HDAC3 selective inhibitor RGFP966 (0.1-10 μM) for 24 h...mRNA sequencing analysis revealed that HDAC3 inhibition modulated neuronal regenerative pathways related to neurogenesis, differentiation, axonogenesis, and dendritic spine density in OBCSs. Our findings highlight the complexity and diversity of the effects of HDAC3 inhibition on AD models and suggest that HDAC3 may have multiple roles in the regulation of APP expression and processing, as well as in the modulation of neuroinflammatory and neuroprotective genes."

Epigenetic controller • Journal • Alzheimer's Disease • CNS Disorders • CNS Tumor • Inflammation • Neuroblastoma • Oncology • Solid Tumor • APP • Aβ42 • HDAC3

Deficiency of histone deacetylases 3 in macrophage alleviates monosodium urate crystals-induced gouty inflammation in mice. (PubMed, Arthritis Res Ther) - "Deficiency of HDAC3 in macrophage alleviates MSU crystals-induced gouty inflammation through inhibition of TLR2/4 driven IL-6/STAT3 signaling pathway, suggesting that HDAC3 could contribute to a potential therapeutic target of gout."

Epigenetic controller • Journal • Preclinical • Gout • Immunology • Inflammation • Inflammatory Arthritis • Rheumatology • HDAC3 • IL1B • IL6 • TLR2 • TNFA

Histone deacetylase 3-specific inhibitor RGFP966 attenuates oxidative stress and inflammation after traumatic brain injury by activating the Nrf2 pathway. (PubMed, Burns Trauma) - "Overall, our findings demonstrate that RGFP966 can mitigate the first brain damage and neurological impairments in TBI. The underlying mechanism involves triggering the Nrf2-mediated AO system and negatively regulating the HMGB1/TLR4-mediated NLRP3 inflammasome pathway."

Epigenetic controller • IO biomarker • Journal • CNS Disorders • Inflammation • Vascular Neurology • HDAC3 • HMGB1 • NLRP3 • TLR4

Endothelial HDAC3 mediates pathological retinal neovascularization via metabolic reprogramming (ARVO 2024) - "Cells were treated with the HDAC3 inhibitor, RGFP966 (2, 8 μM), or DMSO for control... Endothelial HDAC3 mediates pathological retinal angiogenesis under hypoxic conditions possibly via HK2 mediated metabolic reprograming to a glycolytic phenotype and suppression of mitochondrial function. Future experiments will further elucidate the underlying mechanisms. Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand."

Age-related Macular Degeneration • Diabetic Retinopathy • Ophthalmology • Retinal Disorders • Retinopathy of Prematurity • HDAC3 • HK2

A phenotypic screening platform for identifying chemical modulators of astrocyte reactivity. (PubMed, Nat Neurosci) - "Administration of RGFP966, a small molecule HDAC3 inhibitor, blocks reactive astrocyte formation and promotes neuroprotection in vivo in mice. Collectively, these results establish a platform for discovering modulators of reactive astrocyte states, inform the mechanisms that control astrocyte reactivity and demonstrate the therapeutic benefits of modulating astrocyte reactivity for neurodegenerative diseases."

Journal • CNS Disorders • HDAC3