SMYD2 is a protein-lysine N-methyltransferase that regulates diverse cellular processes through methylation of both histone and non-histone proteins. The enzyme methylates histone H3 at lysine 4 and lysine 36, contributing to transcriptional regulation 1. Beyond histones, SMYD2 targets multiple non-histone substrates including p53, PPARγ, Ku70, STAT1, and CHMP2B, demonstrating its broad regulatory scope 2345. Mechanistically, SMYD2 activity is regulated by CDK4/6 phosphorylation, which enhances its enzymatic function 6. The protein plays critical roles in DNA repair through Ku70 methylation in the NHEJ pathway 3, cell cycle regulation via CHMP2B methylation during cytokinesis 5, and metabolic regulation through PPARγ methylation 2. Disease relevance includes roles in pulmonary hypertension, where SMYD2 promotes vascular remodeling 2, hepatic protection during ischemia/reperfusion injury via STAT1 regulation 4, and viral infection susceptibility through TMPRSS2 regulation 7. Clinically, SMYD2 represents a promising therapeutic target, with inhibitors showing efficacy in cancer treatment by enhancing antitumor immunity 3 and reducing SARS-CoV-2 infection 7.