KDM2A is a histone demethylase that catalyzes the removal of dimethyl groups from histone H3 lysine 36, a critical modification for transcriptional regulation and chr11 organization. Beyond its canonical demethylase function, KDM2A regulates circadian gene expression in a catalytically-independent manner and maintains centromeric integrity and genomic stability during mitosis. The enzyme also facilitates ubiquitination and degradation of select phosphorylated proteins through interaction with SCF complexes. KDM2A dysregulation associates with multiple disease contexts. In atherosclerosis, macrophage KDM2A promotes inflammatory response through direct transcriptional regulation of FYN, and KDM2A expression in peripheral monocytes/macrophages predicts disease development and progression 1. In colorectal cancer, KDM2A inhibition upregulates ribosome biogenesis and sensitizes tumors to 5-fluorouracil through RNA damage-dependent mechanisms 2. KDM2A represents a selective vulnerability in alternative lengthening of telomeres (ALT)-dependent cancers, where it facilitates post-recombination telomere de-SUMOylation and cluster dissolution 3. In NSD1-deficient head and neck squamous cell carcinoma, KDM2A inhibition restores T-cell infiltration by reversing repressive histone marks at T-cell chemokine promoters 4. In obesity, myeloid-specific KDM2A knockout promotes M2 macrophage polarization and thermogenesis, protecting mice from diet-induced metabolic disease 5. These findings establish KDM2A as a therapeutic target across multiple cancer and metabolic disease contexts.