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Last update 08 May 2025

KDM4D

Last update 08 May 2025

Basic Info

Synonyms

[histone H3]-trimethyl-L-lysine(9) demethylase 4D, FLJ10251, JHDM3D

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Introduction

Histone demethylase that specifically demethylates 'Lys-9' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-4', H3 'Lys-27', H3 'Lys-36' nor H4 'Lys-20'. Demethylates both di- and trimethylated H3 'Lys-9' residue, while it has no activity on monomethylated residues. Demethylation of Lys residue generates formaldehyde and succinate.

Drugs associated with KDM4D

KDM4D inhibitor (Yunnan University)

Target

KDM4D

Mechanism

KDM4D inhibitors

Active Org.

Yunnan University

Originator Org.

Yunnan University

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

KDM4D therapy (StemCardia)

Target

KDM4D

Mechanism

KDM4D modulators

Active Org.

StemCardia, Inc.

Originator Org.

StemCardia, Inc.

Active Indication

Chronic heart failure

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with KDM4D

100 Translational Medicine associated with KDM4D

0 Patents (Medical) associated with KDM4D

110

Literatures (Medical) associated with KDM4D

01 May 2025·Cellular Immunology

USP14 inhibits sensitization-mediated degradation of KDM4D to epigenetically regulate dendritic cell tolerogenic capacity and mitigates airway allergy

Article

Author: Liu, Le ; Zhang, Wenkai ; Zhang, Aizhi ; Harith, Hanis Hazeera ; Cheng, Liying ; Zhang, Hanqing ; Yang, Pingchang ; Lv, Jieping ; Zhang, Huanping ; Mo, Lihua ; Tham, Chau Ling

Numerous immune disorders are caused by the dysfunction of dendritic cells (DC). The mechanism has not been fully comprehended yet. This research is designed to regulate the epigenetic status of lysine-specific demethylase 4D (KDM4D) to enhance DC's immune tolerogenic capacity. In this study, an airway allergy (AA) mouse model was established with dust mite extracts (DME) as the specific antigen. A mouse strain carrying Kdm4d-deficient DCs was employed in the experiments to assess the role of KDM4D in modulating DC's immune tolerogenic functions. The results showed that mice carrying Kdm4d-deficient DCs (KO mice) showed spontaneous Th2 polarization in the airways. Reduced quantities of KDM4D were detected in airway naive DCs (nDCs) of AA mice. The parameters of AA response had a negative correlation with the quantity of KDM4D. The immune tolerogenic capacity of airway nDCs was impaired in KO mice as well as in AA mice. The Il10 promoter was found to be hypermethylated in airway nDCs of AA mice and KO mice. The low quantity of deubiquitinating enzyme 14 (USP14) was related to the high level of hyper ubiquitination observed in KDM4D in the Il10 promoter locus of airway nDCs of AA mice. Exposure to recombinant USP14 increased the quantity of KDM4D in nDCs, restoring the immune tolerogenic capacity of nDCs in AA mice. In conclusion, dysfunctional tolerogenicity is caused by low levels of KDM4D in airway nDCs from AA mice. USP14 restores the tolerogenic capacity of nDCs in AA mice and mitigates experimental AA.

01 Apr 2025·European Journal of Medicinal Chemistry

Discovery of a first-in-class PROTAC degrader of histone lysine demethylase KDM4

Article

Author: Xu, Shilin ; Yu, Lei ; Zhang, Zhang ; Ren, Ran ; Lai, Yuanhui ; Yang, Xiaolong ; Chen, Zhiwen ; Peng, Lijie ; Sun, Yaoliang ; Rao, Danni ; Wang, Yiting ; Wu, Feifei

Targeting histone lysine demethylase 4 (KDM4) has emerged as a promising approach for cancer therapy. Despite significant progress in developing KDM4 inhibitors, many of these compounds demonstrate poor selectivity or limited cellular efficacy, and none have received approval for marketing. In this study, we designed and synthesized a series of novel KDM4-targeted proteolysis targeting chimeras (PROTAC) degraders, as exemplified by compound 11 (RDN8011). RDN8011 effectively degrades KDM4A-C while sparing KDM4D, and displays potent antiproliferative activity in esophageal cancer cells. Furthermore, this compound inhibits histone H3 lysine demethylation and induces cell cycle arrest and apoptosis. Collectively, this study provides a valuable chemical tool for exploring the functions of KDM4, and presents a novel effective strategy for targeting KDM4 in cancer treatment.

01 Dec 2024·Cellular and Molecular Life Sciences

Iron-dependent KDM4D activity controls the quiescence-activity balance of MSCs via the PI3K-Akt-Foxo1 pathway

Article

Author: Xie, Zhongyu ; Wu, Yanfeng ; Huang, Guo ; Che, Yunshu ; Zheng, Guan ; Shen, Huiyong ; Su, Zepeng ; Lin, Jiajie ; Yu, Wenhui ; Ye, Guiwen ; Li, Jinteng

Iron deficiency is a prevalent nutritional deficit associated with organ damage and dysfunction. Recent research increasingly associates iron deficiency with bone metabolism dysfunction, although the precise underlying mechanisms remain unclear. Some studies have proposed that iron-dependent methylation-erasing enzyme activity regulates cell proliferation and differentiation under physiological or pathological conditions. However, it remains uncertain whether iron deficiency inhibits the activation of quiescent mesenchymal stem cells (MSCs) by affecting histone demethylase activity. In our study, we identified KDM4D as a key player in the activation of quiescent MSCs. Under conditions of iron deficiency, the H3K9me3 demethylase activity of KDM4D significantly decreased. This alteration resulted in increased heterochromatin with H3K9me3 near the PIK3R3 promoter, suppressing PIK3R3 expression and subsequently inhibiting the activation of quiescent MSCs via the PI3K-Akt-Foxo1 pathway. Iron-deficient mice displayed significantly impaired bone marrow MSCs activation and decreased bone mass compared to normal mice. Modulating the PI3K-Akt-Foxo1 pathway could reverse iron deficiency-induced bone loss.

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KDM4D

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