KDM3B (lysine demethylase 3B) is a histone demethylase that specifically removes mono- and dimethyl marks from lysine 9 of histone H3 (H3K9me1/2), thereby regulating chr5 structure and gene transcription 1. This enzymatic activity involves demethylation generating formaldehyde and succinate as byproducts. KDM3B functions as a context-dependent epigenetic regulator with both tumor-suppressive and tumor-promoting roles depending on cancer type 1. Mechanistically, KDM3B controls transcription through H3K9 demethylation and coordinates with other epigenetic factors. For example, KDM3B balances H3K9 methylation at the MLL/KMT2A locus in cooperation with methyltransferase G9a, regulating CTCF occupancy and preventing leukemic amplifications and rearrangements 2. In fusion-positive rhabdomyosarcoma, KDM3B supports PAX3-FOXO1 oncogenic transcriptional activity 3. Clinically, KDM3B shows diverse disease relevance. Dysregulation associates with infertility, obesity, metabolic syndromes, and cancers 1. KDM3B is underexpressed in acute myeloid leukemia with specific translocations 4, while KDM3B-ETF1 fusion promotes breast cancer invasion via WNT/β-catenin pathway activation 5. Genome-wide association studies identified KDM3B SNPs linked to radiation therapy-induced urinary toxicity in prostate cancer patients through mechanisms involving circular RNA regulation and fibrotic responses 67. KDM3B represents a tractable therapeutic target across multiple malignancies.