TRMT61A is the catalytic subunit of the tRNA N1-methyladenosine (m1A) methyltransferase complex, which catalyzes formation of m1A at position 58 in initiator methionyl-tRNA. The protein also functions as part of an mRNA methyltransferase complex that introduces m1A modifications into a small subset of mRNAs harboring tRNA T-loop-like structures at low stoichiometries. TRMT61A has emerged as a significant driver of multiple cancer types. In hepatocellular carcinoma, TRMT6/TRMT61A-mediated m1A methylation promotes liver cancer stem cell self-renewal and tumorigenesis by elevating PPARδ translation and triggering cholesterol synthesis to activate Hedgehog signaling 1. In colorectal cancer, TRMT61A maintains m1A-mediated translational reprogramming that restricts histone synthesis and supports cell cycle progression 2, while also enhancing mRNA stability of ONECUT2 to activate MAPK/ERK signaling 3. In bladder cancer, TRMT6/TRMT61A depletion reduces proliferation and cellular stress resistance 4. In head and neck squamous cell carcinoma, TRMT61A-mediated tRNA m1A promotes MYC protein synthesis and PD-L1 upregulation, contributing to immunotherapy resistance 5. Beyond cancer, TRMT61A-mediated m1A methylation of CAG repeat RNA contributes to neurodegeneration by promoting TDP-43 mislocalization and aggregation 6. Conversely, m1A deficiency impairs mRNA translation and exacerbates protein aggregation during proteotoxic stress 7. Clinically, small-molecule inhibitors targeting TRMT6/TRMT61A and nanoparticle-delivered siRNA approaches show therapeutic promise in cancer models.