SMYD3 is a histone methyltransferase that catalyzes di- and tri-methylation of histone H3 lysine 4 and methylation of histone H4 lysine 5, functioning as a transcriptional amplifier within RNA polymerase complexes. Beyond histone substrates, SMYD3 methylates non-histone proteins including MAP3K2, IRF3, and c-MYC, modulating diverse cellular pathways. In cancer, SMYD3 is frequently overexpressed and acts as an oncogenic driver across multiple tumor types. A meta-analysis of 715 cancer patients showed SMYD3 overexpression was significantly associated with poor overall survival (HR = 1.81) and with lymph node metastasis, larger tumor size, and advanced TNM stage in hepatocellular carcinoma, non-small cell lung carcinoma, esophageal squamous cell carcinoma, glioma, colorectal cancer, and bladder cancer 1. SMYD3 promotes drug resistance by regulating DNA damage response pathways, particularly homologous recombination and non-homologous end-joining 2. In chr1 myeloid leukemia, SMYD3 sustains leukemia stem cell self-renewal by activating fatty acid β-oxidation through the FABP5/PPARD/CPT1A axis 3. Recent evidence indicates SMYD3 also negatively regulates antiviral immunity by catalyzing IRF3 dimethylation, suppressing type I interferon production 4. Multiple SMYD3 inhibitors are under development, with combination therapy targeting SMYD3 alongside standard or targeted treatment showing promise in colorectal, gastric, pancreatic, breast, endometrial, and lung cancer models 2.