TRMT61A is the catalytic subunit of tRNA N1-methyladenosine (m1A) methyltransferase complex that catalyzes formation of m1A58 in initiator methionyl-tRNA 1. The enzyme also mediates m1A methylation of a small subset of mRNAs containing tRNA T-loop-like structures at low stoichiometries 2. TRMT61A functions with TRMT6 to stabilize the m1A methyltransferase complex 3. Clinically, TRMT61A exhibits oncogenic activity across multiple cancer types. In hepatocellular carcinoma, elevated m1A and TRMT6/TRMT61A expression correlate with poor survival, promoting liver cancer stem cell self-renewal through PPARδ-mediated cholesterol and Hedgehog signaling 4. In colorectal cancer, TRMT61A upregulation associates with poor prognosis and promotes tumorigenesis via m1A-dependent mRNA stability of ONECUT2, activating MAPK/ERK signaling 5. TRMT6-mediated tRNA m1A modification restricts histone synthesis and cell cycle progression in CRC 3. In bladder cancer, TRMT6/TRMT61A depletion reduces proliferation and stress resistance 6, while in head and neck squamous cell carcinoma, TRMT61A promotes MYC synthesis and PD-L1 upregulation, enabling immune escape 7. Beyond cancer, TRMT61A-mediated m1A protects against protein aggregation in neurodegenerative contexts and amyloidogenesis 89. These findings identify TRMT61A as a promising therapeutic target across multiple malignancies.