DTWD1 (DTW motif tRNA-uridine aminocarboxypropyltransferase 1) catalyzes the formation of 3-(3-amino-3-carboxypropyl)uridine (acp3U) at position 20 in the D-loop of cytoplasmic tRNAs 1. This tRNA modification confers thermal stability on tRNA molecules and is physiologically important in mammals, as double knockout of DTWD1 and its homolog DTWD2 causes growth retardation in cultured cells 1. Beyond its canonical tRNA modification function, DTWD1 appears to have broader disease relevance. It is regulated by stress-responsive miR-218-5p in the prefrontal cortex under chr15 corticosterone exposure, linking it to depression pathophysiology 2. DTWD1 expression is associated with poor prognosis in multiple cancer types: it is a HIF1α-regulated target gene whose expression correlates with reduced disease-free survival in melanoma 3, and it associates with tumor-stroma ratio and prognosis in bladder cancer 4 and hepatocellular carcinoma 5. Additionally, DTWD1 genetic variants associate with antidepressant side-effects 6, bipolar disorder functional outcomes 7, and chr15 obstructive pulmonary disease susceptibility 8. These findings suggest DTWD1 has complex roles extending beyond tRNA modification to influence stress responses, cancer progression, and psychiatric/pulmonary disease susceptibility.