KDM2A (lysine demethylase 2A) is a histone-modifying enzyme that specifically demethylates H3K36me2, playing crucial roles in epigenetic regulation and cellular homeostasis 1. The enzyme functions as an α-ketoglutarate-dependent dioxygenase, making it susceptible to inhibition by oncometabolites like 2-hydroxyglutarate produced by mutant IDH enzymes 1. KDM2A demonstrates significant disease relevance across multiple pathological contexts. In cancer, it serves as a selective vulnerability for alternative lengthening of telomeres (ALT)-dependent tumors, where it facilitates telomere cluster dissolution through SENP6-mediated SUMO deconjugation 2. Additionally, KDM2A inhibition can enhance T-cell infiltration in NSD1-deficient head and neck squamous cell carcinomas by restoring expression of T-cell chemokines CXCL9 and CXCL10 3. In metabolic disease, myeloid-specific KDM2A deletion protects against diet-induced obesity by promoting macrophage M2 polarization through increased H3K36me2 at the Pparg locus 4. Conversely, KDM2A promotes atherosclerosis by regulating FYN expression and inducing macrophage inflammatory responses 5. Clinically, de novo KDM2A variants cause syndromic neurodevelopmental disorders characterized by intellectual disability, growth restriction, and distinctive facial features, likely through gain-of-function mechanisms 6. KDM2A also modulates cancer cell sensitivity to 5-fluorouracil by regulating ribosome biogenesis 7.