TRIT1 encodes tRNA isopentenyltransferase 1, which catalyzes the transfer of a dimethylallyl group to adenine at position 37 of both cytosolic and mitochondrial tRNAs, generating the modification N6-(dimethylallyl)adenosine (i6A37). This modification is essential for efficient mitochondrial protein translation and energy metabolism. TRIT1 modifies a limited subset of tRNAs, including tRNA(Ser) variants, and is required for selenoprotein expression through modification of selenocysteine-tRNA. Pathogenic loss-of-function mutations in TRIT1 cause a recognizable mitochondrial disorder characterized by myoclonic epilepsy, developmental delay, speech delay, strabismus, and progressive spasticity, with normal lactate levels 1. Defective i6A37 modification impairs translational fidelity and efficiency, leading to oxidative phosphorylation deficiency 2. Noninvasive diagnosis is possible through mass spectrometry analysis of peripheral blood and urine samples, which show decreased i6A and 2-methylthio-i6A modifications 3. In cancer contexts, TRIT1 functions as a candidate tumor suppressor: expression of functional TRIT1 reduced colony formation and tumorigenicity in lung cancer models 4, and genetic ablation of TRIT1 in hepatocellular carcinoma cells triggered ferroptosis through disruption of selenoprotein synthesis 5. Pharmacological targeting of the mevalonate pathway (via 6-FMEV or atorvastatin) to inhibit TRIT1-mediated tRNA modification showed anti-tumor efficacy in HCC models and demonstrated synergistic effects with tyrosine kinase inhibitors and anti-PD-1 immunotherapy 5.