GSKJ4 / Yamagata University - LARVOL DELTA

Epigenetic Targeting of Senescent Cells Prevents the Deleterious Effects of Obstructive Sleep Apnea on Growing Skeleton. (PubMed, Adv Sci (Weinh)) - "Employing both genetic and pharmacological strategies, it is demonstrated that the restoration of H3K27me3 levels via UTX inhibition (achieved through in vivo knockout or GSK-J4 treatment) effectively prevents CIH-induced senescence, promotes osteogenesis, and alleviates bone loss and growth retardation. These findings elucidate a novel epigenetic mechanism that underlies the skeletal impairments associated with CIH and underscore the therapeutic potential of targeting histone methylation to mitigate hypoxia-induced bone defects."

Journal • CNS Disorders • Obstructive Sleep Apnea • Osteoporosis • Pediatrics • Respiratory Diseases • Sleep Disorder • HIF1A

P300/CBP acetyltransferase inhibition and degradation disrupt oncogenic transcriptional programs and reveal epigenetic vulnerabilities in multiple myeloma (ASH 2025) - "Inobrodib (CCS1477), a selective P300/CBP bromodomaininhibitor, has shown promising early clinical activity in relapsed/refractory MM, highlighting thetherapeutic relevance of this axis. However, the effects of more direct P300/CBP targeting—via catalyticinhibition or protein degradation—on chromatin structure and MM lineage survival programs remainincompletely defined.Aims:We aimed to characterize the transcriptional and epigenetic effects of catalytic inhibition and targeteddegradation of P300/CBP in MM, identify determinants of resistance and sensitivity, and explore rationalepigenetic drug combinations.MM cell lines were treated with selective small-molecule P300/CBP catalytic inhibitors (A-485, A-241), thebromodomain inhibitor GNE-781, the P300/CBP degrader dCBP-1, the HDAC3 inhibitor RGFP966, and theKDM6 demethylase inhibitor GSK-J4...Collectively, these findings establish P300/CBP as a critical epigenetic dependency in MM, essential formaintaining enhancer..."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Targeted Protein Degradation • HDAC3 • IRF4 • KDM6A • NCOR1 • SLAMF7 • TNFRSF17

GBM growth mode is governed by epigenetic reprogramming of tumor-associated microglia (SNO 2025) - "Pharmacological inhibition of Kdm6b with GSK-J4 disrupted TAM programming and shifted GBM growth towards a bulk expansion mode. Intriguingly, GBM dissemination was significantly more extensive in juvenile host brains, correlating with elevated Kdm6b expression, pointing to a role of age in microglial programming. Collectively, our data reveal that microglial programming via epigenetic modifications determines GBM invasion modes, offering insights for new therapeutic strategies to halt GBM progression."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor • KDM6B

GBM growth mode is governed by epigenetic reprogramming of tumor-associated microglia (WFNOS 2025) - "Pharmacological inhibition of Kdm6b with GSK-J4 disrupted TAM programming and shifted GBM growth towards a bulk expansion mode. Intriguingly, GBM dissemination was significantly more extensive in juvenile host brains, correlating with elevated Kdm6b expression, pointing to a role of age in microglial programming. Collectively, our data reveal that microglial programming via epigenetic modifications determines GBM invasion modes, offering insights for new therapeutic strategies to halt GBM progression."

Brain Cancer • Glioblastoma • Solid Tumor • KDM6B

KDM6A Modulates Anti-Tumor Immune Response By Integrating Immunogenic Cell Death in Human Acute Myeloid Leukemia (ASH 2023) - "We have identified that in comparison to control AML cells, deficiency of KDM6A (KDM6A-kd) associated with daunorubicin/etoposide-induced ICD, which was manifested by significant increase (2-3 fold, P<0.05) in ecto-CRT, plasma membrane exposure of pE1F2α, HSP70 and HSP90 with extracellular release of HMGB1 and ATP. In addition, olaparib and GSK-J4 treatment showed additive effects in ICD and immune activation using primary AML CD34+ cells. Together, we illustrate that KDM6A regulates ICD through epigenetic mechanisms, while KDM6A deficient AML subtypes could be sensitized with immunomodulatory targeted therapy."

Immunogenic cell death • IO biomarker • Tumor mutational burden • Acute Myelogenous Leukemia • Hematological Malignancies • Immunology • Leukemia • Oncology • ATF4 • CALR • CD34 • CD80 • CD86 • CDC37 • HMGB1 • HSP90AA1 • HSPA5 • IFNB1 • KDM6A • NKG2D • RAET1G • STAT1 • TMB • ULBP1

Epigenetic regulation of MMP-11 and -16 expression in human prostate cancer: the role of KDM6A. (PubMed, Epigenomics) - "GSK-J4 increased histone3 lysine27 trimethylation (H3K27me3) enrichment at MMP-11 and -16 promoters, as shown by Chromatin Immunoprecipitation (ChIP). KDM6A demethylates H3K27me3 at MMP-11 and -16 promoters, sustaining their enhanced expression in PCa and revealing a novel epigenetic mechanism driving metastasis-associated protease expression."

Journal • Benign Prostatic Hyperplasia • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • KDM6A • KDM6B • MMP11 • MMP7

Long intergenic non-protein coding RNA 1949 suppresses rituximab resistance in diffuse large B-cell lymphoma via H3K27me3-mediated ONECUT2 silencing. (PubMed, Am J Transl Res) - "LINC01949 suppresses rituximab resistance in DLBCL by promoting H3K27me3-dependent silencing of ONECUT2. These findings highlight the LINC01949-H3K27me3-ONECUT2 axis as a key epigenetic pathway and suggest potential targets to overcome resistance in DLBCL."

Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ONECUT2 • PCA3

Improving the Efficiency of CRISPR/Cas9-Mediated Non-Homologous End Joining Gene Knockout Using Small Molecules in Porcine Cells. (PubMed, Biomolecules) - "To verify whether small molecules can enhance the efficiency of CRISPR/ Cas9-mediated NHEJ gene editing in porcine cells, this experiment investigated the effects of six small-molecule compounds, namely Repsox, Zidovudine, IOX1, GSK-J4, YU238259, and GW843682X, on the efficiency of CRISPR/Cas9-mediated NHEJ gene editing. We also explored the mechanism of Repsox's effect on the efficiency of NHEJ-mediated gene editing. The results showed that Repsox reduces the expression levels of SMAD2, SMAD3, and SMAD4 in the TGF-β pathway, indicating that Repsox can increase the efficiency of CRISPR NHEJ-mediated gene editing in porcine cells through the TGF-β pathway."

Journal • Preclinical • SMAD2 • SMAD3 • SMAD4 • TGFB1

Epigenetic regulation of TIMP-3 expression in human macrophages via physiological and pharmacological modification of histone3 lysine27 (H3K27). (PubMed, Mol Biol Rep) - "In conclusion GSK-J4 reduces TIMP-3 expression and might therefore paradoxically increase macrophage invasion. By contrast, the HDAC inhibitor MS-275 antagonised the depression of TIMP-3 expression by IFN-γ, which should reduce macrophage invasion."

Journal • CNS Disorders • Depression • Inflammation • Psychiatry • CEBPA • IFNG • IL4 • KDM6B • TIMP3

UTX Epigenetically Imposes a Cytolytic Effector Program in Autoreactive Stem-like CD8+ T cell Progenitors (ENDO 2025) - "Indeed, deletion of UTX function in T cells impairs conversion of Tprog to autoimmune effectors and protects mice from spontaneous diabetes, as well as an aggressive form of autoimmune diabetes induced by anti-PD1 cancer immunotherapy. Furthermore, short-term treatment with UTX inhibitor GSKJ4 similarly protects from T1D, highlighting the therapeutic potential of targeting UTX-mediated mechanisms to break unremitting autoimmune responses."

Diabetes • Immunology • Infectious Disease • Metabolic Disorders • Oncology • Type 1 Diabetes Mellitus • CD8

KDM6A downregulation promotes tumor-prone cytokines expression in cancer-associated fibroblasts by activating enhancers. (PubMed, Cell Death Dis) - "However, the inhibitor GSK-J4, specific for both KDM6A and KDM6B, reduces IGF1 expression, indicating that KDM6B compensates for the demethylase function of KDM6A but cannot replace KDM6A to maintain the homeostasis of COMPASS and polycomb repressive complexes. These findings suggest a metabolism-related epigenetic mechanism for cytokine expression, where reduced KDM6A levels enhance the tumor-promoting effect of CAFs. This may provide insights into why colon cancer is more prevalent in men than in women, since KDM6A is an X-chromosome-associated gene."

Journal • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • CAFs • IGF1 • KDM6A • KDM6B • SFRP2 • TGFB1 • WDR5

Lysine demethylase 6 (KDM6): A promising therapeutic target in autoimmune disorders and cancer. (PubMed, Biomed Pharmacother) - "Recent efforts to exploit this duality include developing small-molecule inhibitors, notably GSK-J4, which block KDM6 demethylase activity and show promising therapeutic effects in models of chronic inflammation and cancer. Nonetheless, challenges such as incomplete target specificity, the interplay with other epigenetic mechanisms, and variations in tumor microenvironment emphasize the complexity of translating these findings into clinical practice. This review highlights the structural features, regulatory mechanisms, and disease associations of KDM6 demethylases, positioning them as compelling biomarkers and therapeutic targets at the intersection of autoimmunity and cancer."

Journal • Review • Bladder Cancer • CNS Disorders • Hematological Disorders • Hematological Malignancies • Immunology • Inflammatory Arthritis • Lupus • Multiple Sclerosis • Oncology • Rheumatoid Arthritis • Rheumatology • Solid Tumor • Systemic Lupus Erythematosus • KDM6A • KDM6B

H3K27me3 modulates trained immunity of monocytes in HDM-allergic diseases. (PubMed, Front Immunol) - "Finally, the administration of GSK-J4, which upregulates H3K27me3 level in murine monocytes, attenuated the inflammatory response in vitro and in vivo. Our study confirms that H3K27me3 methylation modulates the trained immunity in monocytes and regulates HDM-allergic diseases through an inflammatory-dependent mechanism."

Journal • Allergy • Food Hypersensitivity • Inflammation

Targeted inhibition of WIP1 and histone H3K27 demethylase activity synergistically suppresses neuroblastoma growth. (PubMed, Cell Death Dis) - "Finally, this drug combination was confirmed to reduce tumor growth in zebrafish xenograft experiments. In conclusion, the combination of the WIP1 inhibitor SL-176 and the epigenetic modifier GSK-J4 induces synergistic cytotoxicity in neuroblastoma cells by potentiating p53 downstream effects."

Journal • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • CDKN1A • KDM6B • PPM1D

H3K27-me3 Inhibition Induces YTHDF2-Mediated Decay of m6A-Marked Severe Acute Respiratory Syndrome Coronavirus 2 Transcripts. (PubMed, J Med Virol) - "The application of the H3K27-demethyltransferase or KDM6A/B inhibitor GSK-J4 can restore H3K27-me3 levels and mitigating the decay of viral mRNA in UNC1999-treated SARS-CoV-2-infected cells. Furthermore, long-term sequential passage (P = 50) of the virus in the presence of UNC1999 did not yield any UNC1999-resistant SARS-CoV-2 mutants. In conclusion, by integrating transcriptomics, molecular virology and functional analyses, we for the first time demonstrated that inhibition of H3K27-me3 induces m6A-mediated decay of SARS-CoV-2 transcripts, highlighting UNC1999 as novel antiviral candidate against SARS-CoV-2."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • KDM6A • YTHDF2

The Histone Demethylase Inhibitor GSK-J4 Attenuates Periodontal Bone Loss and Inflammation in a Rat Model of Periodontitis. (PubMed, Curr Med Sci) - "The histone demethylase inhibitor GSK-J4 attenuated periodontal bone loss and inflammation in a rat periodontitis model by targeting JMJD3."

Journal • Preclinical • Dental Disorders • Inflammation • Oncology • Osteoporosis • Periodontitis • KDM6B • TNFA

Epigenetic dynamics in meniscus cell migration and its zonal dependency in response to inflammatory conditions. (PubMed, APL Bioeng) - "We further identified potential therapeutic targets by using epigenetic drugs, GSKJ4 (a histone demethylase inhibitor) and C646 (a histone acetyltransferase inhibitor), which restored inner meniscus cell migration under inflammatory conditions, highlighting their potential in treating meniscus tears...Overall, our findings elucidate the intricate interplay between epigenetic mechanisms and meniscus cell migration, along with its meniscus zonal dependency. This study provides insight into potential targets for enhancing meniscus repair and regeneration, which may lead to improved clinical outcomes for patients with meniscus injuries and osteoarthritis."

Journal • Immunology • Oncology • Osteoarthritis • Pain • Rheumatology • TNFA

Inhibition of KDM6B prevents osteoarthritis by blocking growth plate-like H3K27me3 loss in bivalent genes. (PubMed, Sci China Life Sci) - "Finally, a KDM6B inhibitor GSK-J4 prevented the H3K27me3 loss and cartilage damage in the rat OA model. Our results reveal an inherited bivalent epigenetic signature on developmental genes that makes articular chondrocytes prone to hypertrophy and contributes to a promising epigenetic therapy for OA."

Journal • Gene Therapies • Immunology • Osteoarthritis • Pain • Rheumatology • KDM6B

Bisphenol B restrains rat leydig cell function via H3K27me3/H3K9me3 histone modifications. (PubMed, Ecotoxicol Environ Saf) - "Furthermore, adult Leydig cells were extracted and cultured with BPB (0, 10, 50, 100, and 200 μM) alone or in combination with H3K27me3 antagonist GSK-J4...BPB could potentially hinder the growth and function of Leydig cells by modulating H3K27me3 and H3K9me3. The findings of the study indicate the involvement of histone methylation (H3K27me3) in BPB-induced steroidogenic dysfunction, emphasizing the correlation between histone modifications and male reproductive toxicity."

Journal • Preclinical • CYP17A1 • EEF1A1 • SCARB1 • SOX9 • SUZ12

Targeting the interplay between replication stress (RS) induced DNA damage response (DDR) and epigenetics in children with high-risk neuroblastoma and sarcoma (LCC 2025) - "ATR inhibitor (AZD6738/Cerelasertib) combinations with epigenetic drugs causing chromatin closing: bromodomain/histone acetyltransferase (HAT) inhibitors (BI-894999, CBP30, BMS-986158), histone demethylase (KDM) inhibitors (GSK-J4), or chromatin opening: DNA methyltransferase inhibitors (OTS186935, Decitabine), histone deacetylase (HDAC) inhibitors (Panobinostat, Entinostat, Vorinostat) were tested in neuroblastoma and sarcoma cell lines. These combinations offer superior efficacy than either drug alone. Functional studies will elucidate mechanisms responsible for observed synergy, and effective combinations will be validated in vivo."

Clinical • CNS Tumor • Neuroblastoma • Oncology • Pediatrics • Rhabdomyosarcoma • Sarcoma • Solid Tumor • MYCN

Inhibiting H3K27 Demethylases Downregulates CREB-CREBBP, Overcoming Resistance in Relapsed Acute Lymphoblastic Leukemia. (PubMed, Cancer Med) - "This study proposes H3K27 demethylase inhibition as a potential treatment strategy for patients with treatment-resistant ALL, using CREBBP as a biomarker for drug response and combining GSK-J4 with venetoclax and navitoclax as synergistic partners."

IO biomarker • Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BCL2L1 • CREBBP

Combined anti-leukemic effect of gilteritinib and GSK-J4 in FLT3-ITD+ acute myeloid leukemia. (PubMed, Transl Oncol) - "In addition, gilteritinib or GSK-J4 monotherapy increases reactive oxygen species (ROS) production, and the combination has a synergistic effect, accelerating leukemic cell death. Our study provides proof that the combined therapy of gilteritinib and GSK-J4 has a synergistic antileukemic effect on FLT3-ITD+ AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CASP9 • FLT3 • KDM6B

Prenatal dexamethasone exposure reduces osteoprogenitor proliferation in mice via histone modifications at the Mkp-1 gene locus. (PubMed, Commun Biol) - "Prenatal dexamethasone exposure (PDE) has long-term consequences in bone development, though the underlying mechanisms remain unclear. Importantly, restoring histone methylation balance with PFI-90 or GSK-J4 treatment blocks the inhibitory effects of PDE on MAPK signaling in osteoprogenitors, and mitigates the detrimental impact of PDE on osteoprogenitor proliferation and bone development in the offspring. This study provides new insights into the epigenetic mechanism by which PDE disrupts long-term programming of fetal osteoprogenitor proliferation, ultimately impairing long bone growth in offspring."

Epigenetic controller • Journal • Preclinical

Suppression of the H3K27me3 demethylase disrupts diapause formation in mosquito Culex pipiens. (PubMed, Insect Biochem Mol Biol) - "In the present study, we employed the effective histone lysine demethylase inhibitor GSK-J4 to assess the functions of H3K27me3 levels in the fat body on diapause initiation and phenotypes in Cx...Together, these findings propose a crucial role for H3K27me3 in diapause formation, particularly related to energy metabolism. Our results provide a potential target for novel vector control strategies for this species."

Journal

KDM6B-Mediated HADHA Demethylation/Lactylation Regulates Cementogenesis. (PubMed, J Dent Res) - "In vivo, injection of GSK-J4 into mice detected the influence of KDM6B on cementum formation...Overexpression of Hadha and the addition of lactate sodium could rescue the inhibition of mineralization by knockdown of Kdm6b. In summary, during cementoblast mineralization, KDM6B regulates HADHA by mediating histone demethylation and lactylation, thereby upregulating FAO and thus promoting mineralization."

Journal • Dental Disorders • Periodontitis • KDM6B