SMYD1 is a striated muscle-specific histone methyltransferase essential for cardiac and skeletal muscle development 1. As a SET and MYND domain-containing protein, SMYD1 catalyzes mono-, di-, and trimethylation of histone H3 at lysine 4 (H3K4) to activate gene expression, including Isl1 during early heart development through interaction with ASH2L 1. Beyond histone substrates, SMYD1 methylates non-histone proteins including the skeletal muscle transcription factor skNAC at K1975, promoting myoglobin transcription 2, and catalyzes mono-methylation of myosin heavy chain at K35, which is critical for sarcomere assembly and thick filament formation in both zebrafish and human cardiomyocytes 3. SMYD1 also functions as a transcriptional repressor by associating with HDAC and CHD4 to suppress genes involved in glycolysis, hypoxia response, and angiogenesis 14. SMYD1 deletion causes embryonic lethality with severe cardiac structural defects including outflow tract truncation and impaired second heart field expansion 1. Clinically, SMYD1 expression is downregulated in chr2 nicotine exposure 5, and resistance training upregulates SMYD1 to mitigate age-related oxidative and endoplasmic reticulum stress in cardiac tissue 6. SMYD1 overexpression in engineered human pluripotent stem cell-derived cardiomyocytes enhances contractile function and maturation 7, suggesting therapeutic potential for cardiomyopathies and muscle disorders.