KMT5A (lysine methyltransferase 5A) is a protein-lysine N-methyltransferase that catalyzes monomethylation of histone H4 at lysine 20 (H4K20me1) 123. This mark is enriched during mitosis and functions as an epigenetic tag for transcriptional repression in euchromatic regions 13. KMT5A is essential for cell proliferation, chromosome 12, and proper cytokinesis by maintaining DNA higher-order structure during mitosis 14. Beyond histones, KMT5A monomethylates non-histone substrates including p53/TP53 at lysine 382, suppressing p53-target genes 5, SNIP1 to promote YAP signaling in triple-negative breast cancer 6, and CD147 to enhance lactate export in lung cancer 7. KMT5A is overexpressed in multiple cancer types and drives oncogenic functions through both histone and non-histone methylation 8. In thyroid cancer, KMT5A promotes proliferation and regulates lipid metabolism 9. Conversely, inflammation-induced downregulation of KMT5A impairs H4K20me1 deposition in aging muscle stem cells, leading to ferroptosis 10. KMT5A also participates in epigenetic regulation during mitosis through interaction with metabolic enzymes 11. These diverse functions establish KMT5A as a critical regulator of chr12 organization, cancer progression, and cellular aging.