Identification of Circulating tRNA-Derived Small RNAs As Potential Biomarkers for Sepsis-Induced Acute Respiratory Distress Syndrome

Abstract

Abstract Sepsis-induced acute respiratory distress syndrome (ARDS) can significantly exacerbate disease severity and elevate patient mortality. However, the precise molecular mechanisms driving this phenomenon remain unclear. Recently, circulating extracellular vesicles (EVs) have emerged as carriers of tRNA-derived small RNAs (tsRNAs), a novel class of non-coding RNAs (ncRNAs). Nonetheless, the functional roles of these tsRNAs in sepsis-induced ARDS remain poorly defined. In this study, we collected peripheral blood samples from both healthy subjects and sepsis-induced ARDS patients to profile EV-encased tsRNAs, including tRNA-related fragments (tRFs) and tRNA halves (tiRNAs). Analysis revealed a total of 456 tRFs/tiRNAs in circulating EVs, with only one upregulated tsRNA and 22 downregulated tsRNAs in plasma EVs isolated from sepsis-induced ARDS patients (S-EVs) compared to healthy donor controls (H-EVs). In addition, higher levels of tiRNA-1:34-Glu-CTC-1-M2 and lower levels of tRF-52:71-chrM.Pro-TGG, tRF-1:28-chrM.Ser-TGA, tRF-60:76-Lys-TTT-3-M2, tRF-58:75-Cys-GCA-11-M7, tRF-1:15-Val-TAC-1-M3, and tRF-59:76-Tyr-GTA-1-M2 in S-EVs were validated by RT‒qPCR and further scrutinized through bioinformatics analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses demonstrated that the differentially expressed tsRNAs were primarily associated with Wnt, Hippo, circadian rhythm, FoxO, and ferroptosis signaling pathways. Notably, cellular activities implicated in these signaling pathways encompassed inflammation, oxidative stress, glucose metabolism, autophagy, and immune regulation. In summary, this study identifies a specific set of plasma EV-derived tsRNAs that potentially modulate signaling pathways relevant to sepsis-induced ARDS. Thus, tsRNAs may play a crucial role in the pathogenesis of sepsis-induced ARDS and hold significant potential as diagnostic biomarkers.