Kdm4b, a member of the KDM4 family also known as JMJD2, is a lysine-specific demethylase. It specifically targets di-and tri-methylated lysine 9 on histone H3 (H3K9me3), reversing a modification crucial for heterochromatin definition and gene repression. This histone demethylation process is involved in regulating nuclear processes like gene transcription, DNA replication, and repair, and is important for normal development and can contribute to cancer progression [1,4,5].

In skeletal aging, loss-of-function of Kdm4b in mesenchymal stromal cells (MSCs) exacerbates the bone-fat imbalance and MSC exhaustion. Kdm4b-deficient MSCs show reduced bone formation, increased marrow adiposity, and impaired self-renewal due to increased H3K9me3 and senescence-associated heterochromatin foci formation [2]. In oral bones, loss of Kdm4b in oral MSCs (OMSCs) inhibits osteogenesis, promotes adipogenesis and OMSC senescence, disturbing the bone-fat balance in the mandible [7].

In a heterozygous mouse model of Kdm4b (Kdm4b+/-), disruptions lead to reduced total brain volume, decreased hippocampal dentate gyrus size, partial agenesis of the corpus callosum, and ventriculomegaly, mirroring the global developmental delay and neuroanatomical defects seen in humans with Kdm4b variants [3].

In glioblastoma, silencing Kdm4B inhibits cell survival, proliferation, migration, and invasion, suggesting its essential role in tumorigenic activity [6]. In prostate cancer, knockdown of Kdm4B significantly inhibits cell proliferation, while its overexpression promotes cell proliferation by activating autophagy [8]. In uterine corpus endometrial carcinoma, Kdm4B is overexpressed and associated with poor prognosis, and is enriched in immune-related biological processes and signaling pathways [9].

In conclusion, Kdm4b plays diverse and crucial roles in normal development and disease through its histone demethylation function. Studies using gene knockout (KO) or conditional knockout (CKO) mouse models have revealed its significance in skeletal aging, neurodevelopment, and cancer progression. These findings enhance our understanding of the underlying mechanisms and provide potential therapeutic targets for related diseases.