KDM6B (lysine demethylase 6B) is a histone demethylase that specifically removes di- and trimethyl groups from lysine 27 of histone H3 (H3K27me2/me3), playing crucial roles in chr17 remodeling and gene expression regulation 1. The enzyme functions as an α-ketoglutarate-dependent demethylase, utilizing this metabolite as a cofactor for its catalytic activity 2. KDM6B demonstrates significant clinical relevance through its involvement in multiple disease processes. De novo variants in KDM6B cause a neurodevelopmental disorder characterized by cognitive deficits, hypotonia, and behavioral abnormalities, though the phenotypic spectrum is broader than initially described 3. In cancer, KDM6B promotes tumor progression through multiple mechanisms: it enhances osteosarcoma metastasis by demethylating the LDHA promoter 1, drives immunosuppression in prostate cancer through iron-dependent activation 4, and its downregulation by cancer-derived exosomal miR-138-5p promotes tumor-associated macrophage M2 polarization 5. Additionally, KDM6B regulates hepatic autophagy and lipid metabolism through FGF21 signaling 6 and contributes to interferon-stimulated gene expression in systemic lupus erythematosus 2. These diverse functions establish KDM6B as a critical epigenetic regulator with significant therapeutic potential across multiple pathological conditions.