KDM5B is a histone H3K4 demethylase that regulates gene expression through removal of methylation marks at lysine 4 of histone H3 1. It demethylates trimethylated, dimethylated, and monomethylated H3K4 modifications but does not target H3K9 or H3K27 1. KDM5B functions as a transcriptional corepressor, suppressing tumor suppressor genes like BRCA1 and HOXA5 in breast cancer cells 1, while its role in melanoma appears context-dependent. Mechanistically, KDM5B promotes immune evasion in melanoma by recruiting SETDB1 to silence retroelements in a demethylase-independent manner, and depletion of KDM5B derepresses these elements to trigger interferon responses and enhance immunotherapy sensitivity 2. In nasopharyngeal carcinoma, KDM5B stabilized by deubiquitinase USP7 promotes cisplatin resistance by reducing H3K4me3 at the ZBTB16 promoter, ultimately increasing TOP2A expression 3. KDM5B also drives smooth muscle phenotypic transformation in diabetic vasculature 4 and hijacking by Epstein-Barr virus enhances metastatic potential 5. During early embryogenesis, KDM5B removes broad H3K4me3 domains required for zygotic genome activation 6. Clinically, biallelic KDM5B variants cause autosomal recessive intellectual developmental disorder 65 with developmental delay and facial dysmorphism 78, while dominant variants associate with neurodevelopmental disorders and growth abnormalities 8.