SMYD5 is a protein-lysine methyltransferase with dual roles in ribosomal translation and epigenetic regulation. Its primary function is catalyzing trimethylation of lysine-22 on ribosomal protein RPL40 (rpL40K22me3), which enhances translation elongation and protein synthesis output 12. This ribosomal methylation activity promotes malignant progression in gastric adenocarcinoma and hepatocellular carcinoma by reprogramming oncogenic protein synthesis 12. SMYD5 also functions as a histone methyltransferase, catalyzing H3K36me3 and H4K20me3 formation to regulate gene expression and maintain genome stability in embryonic stem cells 3. Disease relevance is substantial across multiple pathologies. In cancer, SMYD5 upregulation correlates with poor prognosis in HCC and GAC; SMYD5 depletion blocks metastatic disease and sensitizes tumors to PI3K-mTOR inhibitors 124. In rheumatoid arthritis, SMYD5 promotes fibroblast proliferation and inflammation by methylating FoxO1 and upregulating HK2-mediated glycolysis 5. SMYD5 exacerbates inflammatory bowel disease by methylating PGC-1α, accelerating its degradation and impairing mitochondrial biogenesis in intestinal epithelia 6. SMYD5 also regulates the hypothermia response by repressing the neuroprotective gene SP1 through H3K36me3 7. Clinically, SMYD5 represents a therapeutic target; its inhibition combined with immunotherapy or mTOR inhibitors shows promise in cancer and inflammatory disease models.