A tRNA-derived fragment tRF3019a promotes LUAD metastasis by stabilizing hnRNPK and enhancing MYH11 expression

tRNA-derived fragments (tRFs) have been shown to play important regulatory roles in cancer biology. However, the impact of tRFs on lung adenocarcinoma (LUAD) remains largely unexplored. The differential expression of tRF3019a, a tRNA fragment derived from tRNA-Ala (AGC), was identified through database mining and subsequently validated by quantitative reverse transcription PCR (qRT–PCR) in pathological tissues obtained from 100 patients with LUAD. The role of tRF3019a in LUAD metastasis was assessed through both in vitro and in vivo experiments. A comprehensive investigation of its regulatory function involved RNA pulldown assays, mass spectrometry, RNA immunoprecipitation (RIP), western blotting, chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), and rescue assays. tRF3019a expression was significantly elevated in LUAD tumor tissues and was associated with advanced disease stage and metastatic progression. Higher tRF3019a expression correlated with shorter overall survival and disease-free survival. Functionally, tRF3019a enhanced LUAD cell migration and invasion both in vitro and in vivo. Mechanistically, tRF3019a interacted with heterogeneous nuclear ribonucleoprotein K (hnRNPK) and inhibited its ubiquitin-mediated proteasomal degradation, leading to increased hnRNPK protein stability. This was accompanied by changes in epithelial–mesenchymal transition (EMT)-associated markers, including increased N-cadherin and vimentin and decreased E-cadherin. Furthermore, tRF3019a enhanced hnRNPK-associated transcriptional regulation of the myosin heavy chain 11 (MYH11) gene, contributing to the pro-metastatic phenotype of LUAD cells. tRF3019a promotes LUAD progression and metastasis by stabilizing hnRNPK and enhancing hnRNPK-associated transcriptional regulation of MYH11. These findings identify a previously unrecognized tRF3019a–hnRNPK–MYH11 regulatory axis involved in LUAD metastasis.