SMYD4 is a protein-lysine N-methyltransferase that functions as both a histone and non-histone methyltransferase with critical roles in cardiac development and cancer regulation 1. The protein monomethylates key substrates including PRMT5, modulating its transcriptional activity and forming regulatory feedback loops 1. SMYD4 also monomethylates MYH9, promoting its ubiquitination and degradation, which inhibits WNT signaling pathway activation 2. In cardiac development, SMYD4 acts as a key epigenetic regulator through dual activities as a methyltransferase and negative regulator of HDAC1, with loss-of-function mutations causing severe cardiac malformations including defects in left-right patterning and hypoplastic ventricles 3. Functionally, SMYD4 serves as a tumor suppressor in most cancer types, showing consistent downregulation and heterozygous loss across solid tumors 4. In breast cancer, SMYD4 disruption leads to tumorigenesis, while re-expression suppresses tumor growth 5. However, in hepatocellular carcinoma, SMYD4 acts as an oncogene, promoting proliferation and metastasis through PRMT5 activation 1. Clinically, SMYD4 expression levels correlate with patient prognosis, with low expression associated with poor survival outcomes in certain tumor types 4.