SMYD3 is a histone methyltransferase that catalyzes di- and tri-methylation of histone H3 lysine 4 (H3K4me3) and methylates histone H4 lysine 5, functioning as a transcriptional amplifier within RNA polymerase II complexes 12. Beyond histones, SMYD3 methylates non-histone substrates including MAP3K2, IRF3, c-MYC, and RNF113A, modulating diverse signaling pathways 3456. SMYD3 is significantly upregulated across multiple cancer types, with overexpression associated with poor overall survival (HR=1.81) and adverse clinicopathological features including lymph node metastasis, larger tumor size, and advanced TNM stage 7. In solid tumors, SMYD3 acts as a nuclear transcriptional amplifier of oncogenes and proliferation-controlling genes; in lung and pancreatic cancers, it functions cytoplasmically to potentiate oncogenic Ras/ERK signaling 3. In chr1 myeloid leukemia, SMYD3 maintains leukemia stem cell self-renewal by activating fatty acid β-oxidation through the FABP5/PPARD/CPT1A axis 8. Conversely, SMYD3 negatively regulates antiviral immunity by dimethylating IRF3, suppressing type I interferon production 4. These multifaceted roles establish SMYD3 as both a cancer prognostic biomarker and emerging therapeutic target.