tRNA-derived small RNAs in vascular smooth muscle cell phenotypic switching and vascular remodelling

tRNA-derived small RNAs (tsRNAs) are noncoding RNAs generated from precursor or mature tRNAs. Basal tsRNA levels are detectable under physiological conditions, but their production increases sharply under cellular stress. tsRNAs regulate gene expression through miRNA-like targeting, translational control, and intercellular communication. In vascular remodelling disorders-including atherosclerosis (AS), aortic dissection (AD), and in-stent restenosis (ISR)-vascular smooth muscle cells (VSMCs) undergo phenotypic switching from contractile to synthetic states. Pulmonary hypertension (PH) shares similar phenotypic features, but the current evidence on the role of tsRNAs in PH remains largely predictive. Several experimentally studied tsRNAs affect VSMC phenotypic behaviour in disease- and context-dependent manners by targeting key signalling molecules, including STAT4, FMOD, FAS, and CBX3/HP1γ, with downstream consequences for contractile gene expression and proliferative behaviour. Notably, these tsRNAs act bidirectionally: 5'-tiRNA-Cys-GCA and tRF-Glu-CTC (via FMOD targeting) suppress the synthetic phenotype and neointimal formation, whereas tRF-Gln-CTG promotes it. We propose an evidence-mapped conceptual framework organized by regulatory layers-transcriptional, posttranscriptional, and chromatin-associated regulation-while acknowledging that cross-layer interactions remain to be experimentally verified. Clinically, tsRNAs hold promise as liquid biopsy biomarkers and therapeutic targets, but the current evidence is preliminary and requires validation against established biomarkers before translational application. This review synthesizes the current evidence on tsRNA biology in the context of VSMC phenotypic switching and outlines a roadmap for future research.