METTL1-regulated tRF-5001b suppresses lung adenocarcinoma by impairing QARS1 interaction with tRNAGln and inhibiting HMGA2 translation

Background Lung adenocarcinoma (LUAD) remains the leading cause of cancer-related mortality worldwide, yet the impacts of tRNA-derived fragments (tRFs) on its progression are not fully understood. This study aimed to investigate the role of tRF-5001b in LUAD. Methods The expression of tRF-5001b in LUAD tissues was analyzed using public datasets and validated by Northern blotting. The biological functions of tRF-5001b, QARS1, and HMGA2 were evaluated using EdU, transwell, and CCK-8 assays in vitro, as well as subcutaneous and intravenous injection models in vivo. RNA fluorescence in situ hybridization and immunofluorescence were performed to determine the subcellular localization of tRF-5001b and QARS1. The expression levels of METTL1, WDR4, QARS1, and HMGA2 were examined by qRT-PCR and Western blotting. RNA immunoprecipitation, RNA pull-down, silver staining, co-immunoprecipitation, and molecular docking were conducted to investigate the interaction between tRF-5001b and QARS1. Puromycin incorporation assays were performed to assess the effect of tRF-5001b on global protein translation. Results tRF-5001b was significantly downregulated in LUAD tissues and exhibited tumor-suppressive effects by inhibiting tumor cell proliferation, migration, and invasion both in vitro and in vivo. Mechanistically, tRF-5001b competitively disrupted the interaction between QARS1 and tRNA Gln , thereby suppressing HMGA2 translation and attenuating LUAD progression. Furthermore, METTL1 was identified as a negative regulator of tRF-5001b biogenesis through catalyzing m 7 G modification of tRNA-Tyr-GTA. Conclusion This study identifies tRF-5001b as a suppressor of LUAD progression through inhibition of HMGA2 translation and highlights METTL1 as a key regulator of its biogenesis. These findings provide new insights into tRF-mediated molecular mechanisms and suggest potential therapeutic targets for lung adenocarcinoma.