TRMT5 (tRNA methyltransferase 5) is a nuclear-encoded protein that catalyzes N1-methylguanosine (m1G) methylation at position 37 of guanosine in mitochondrial and nuclear tRNAs 1. This methylation represents the first step in wybutosine biosynthesis, a modified base required for accurate tRNA anticodon loop decoding. TRMT5 functions primarily in the mitochondrial matrix, where it is essential for dynamic upregulation of mitochondrial messenger RNA translation and oxidative phosphorylation 1. Dysfunction of TRMT5 leads to multiple disease phenotypes. Pathogenic TRMT5 mutations cause a complex inherited neuropathy syndrome characterized by infantile-onset demyelinating peripheral neuropathy, developmental delay, intellectual disability, and cerebellar abnormalities 2. Additionally, TRMT5 mutations are associated with isolated porto-sinusoidal vascular disorder (PSVD), suggesting immune cell involvement in disease pathogenesis 3. In obesity-related renal injury, circulating B cell-derived miR-3960 targets TRMT5, impairing mitochondrial tRNA methylation and causing electron transport chain dysfunction in renal tubular cells 4. Clinically, TRMT5 emerges as a therapeutic target in cancer. Elevated TRMT5 expression correlates with poor prognosis in hepatocellular carcinoma and promotes drug tolerance in acute myeloid leukemia through mitochondrial metabolic upregulation 51. TRMT5 depletion combined with chemotherapy synergistically induces cell death in drug-resistant leukemia cells, identifying TRMT5 as a promising therapeutic target.