A Specific tRNA Half, 3' tiRNA ‐ GlyGCC , Regulates Hypoxic Pulmonary Artery Smooth Muscle Cell Proliferation via Myrf‐Mediated Endoplasmic Reticulum Stress

Pulmonary artery smooth muscle cell (PASMC) proliferation is a hallmark of the pathogenesis of hypoxic pulmonary hypertension (PH), and endoplasmic reticulum stress (ERS) plays a crucial role. Many studies have implicated that tRNA‐derived fragment, tiRNAs, in a variety of biological processes, but their roles in hypoxia‐induced PASMC ERS and proliferation have not been investigated. In this study, we identified a significantly upregulated 3′tiRNA‐GlyGCC in hypoxic mouse lung tissues using Arraystar small RNA microarray analysis. Functional assays, including CCK8, EdU incorporation, Western blot, and immunofluorescence, demonstrated that inhibition of 3′tiRNA‐GlyGCC reversed hypoxia‐induced ERS and proliferation in PASMCs. Mechanistically, 3′tiRNA‐GlyGCC interacts with the eukaryotic translation elongation factor 1 alpha 1 (Eef1a1) protein and reduces the binding capacity between Eef1a1 and myelin regulatory factor (Myrf) mRNA, leading to decreased stability of Myrf mRNA. Additionally, 3′tiRNA‐GlyGCC targets Myrf mRNA and inhibits its expression. We further verified that angiogenin (Ang) mediated the biogenesis of 3′tiRNA‐GlyGCC under hypoxic conditions. Collectively, these findings highlight a novel mechanism underlying PASMC ERS and proliferation and suggest that 3′tiRNA‐GlyGCC could serve as a potential therapeutic target for hypoxic PH.