LAGE3 is a component of the EKC/KEOPS complex required for t(6)A37 tRNA modification, functioning as a dimerization module 12. The complex catalyzes transfer of a threonylcarbamoyl group to adenosine at position 37 in tRNAs reading adenine-starting codons, maintaining translational fidelity 12. Mutations in LAGE3 cause Galloway-Mowat syndrome 2 (X-linked), characterized by early-onset nephrotic syndrome and primary microcephaly 34. LAGE3 deficiency impairs protein translation, induces endoplasmic reticulum stress, and activates DNA-damage response and apoptosis pathways, with podocyte cytoskeletal defects contributing to kidney disease 3. Beyond monogenic disease, LAGE3 is significantly upregulated in multiple solid tumors including papillary thyroid cancer and hepatocellular carcinoma (HCC) 56. In HCC, high LAGE3 expression promotes proliferation, migration, and angiogenesis via PI3K/AKT/mTOR and Ras/RAF/MAPK pathways, correlating with poor prognosis 67. LAGE3 stabilizes VEGFA mRNA to enhance angiogenesis 8, and its knockdown reduces oncogenic phenotypes 5. This dual role—critical for tRNA modification in normal physiology but promoting malignancy when dysregulated—positions LAGE3 as both a monogenic disease gene and emerging therapeutic target.