tRF-GluCTC promotes VSMC apoptosis and oxidative stress by targeting TYRO3 in intracranial aneurysm.

Abstract

BACKGROUND AND AIMS: tRNA-derived small RNAs (tsRNAs) have attracted growing attention for their involvement in various diseases, but their role in intracranial aneurysm (IA) remains unclear. This study aimed to investigate the potential of tsRNAs, specifically tRF-GluCTC, in the development and progression of IA. METHODS: High-throughput sequencing was performed to identify differentially expressed tsRNAs in the plasma exosomes of IA patients. The expression of tRF-GluCTC was analyzed in both exosomes and IA tissues. Functional assays in vascular smooth muscle cells (VSMCs) were conducted to examine the effects of tRF-GluCTC on apoptosis, oxidative stress, and inflammation. Bioinformatics analysis was used to predict and validate the target gene of tRF-GluCTC. In vivo experiments were carried out using an IA animal model to assess the impact of tRF-GluCTC knockdown on IA formation and vascular pathology. RESULTS: tRF-GluCTC was found to be significantly upregulated in both plasma exosomes and IA tissues. Functional assays revealed that tRF-GluCTC promotes apoptosis, oxidative stress, and inflammation in VSMCs. Mechanistically, tRF-GluCTC was shown to bind to the 3'UTR of its target gene TYRO3, leading to its downregulation and suppression of the PI3K/Akt signaling pathway, which modulates VSMC function. In animal models, knockdown of tRF-GluCTC attenuated IA formation, improved vascular pathology, and reduced VSMC apoptosis and oxidative stress. Additionally, both exosomal and free plasma tRF-GluCTC levels were elevated in IA patients, with exosomal tRF-GluCTC showing superior diagnostic performance compared to free plasma tRF-GluCTC. CONCLUSION: These findings highlight the critical role of tRF-GluCTC in the pathogenesis of IA and its potential as a novel biomarker for diagnosis. Additionally, tRF-GluCTC may serve as a promising therapeutic target for the treatment of IA.