B cell-derived exosomal tRNA-Pro-TGG served as a non-invasive biomarker and mediator of inflammation in progressive IgA nephropathy.

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and a leading cause of end-stage renal disease globally. Although mesangial IgA deposition defines its pathology, this alone does not predict disease progression. Current biomarkers lack specificity for forecasting outcomes or guiding early intervention. Recent advances have highlighted the potential of exosome-derived tRNA-derived small RNAs (tsRNAs) as novel diagnostic tools and mediators of disease processes, but their role in IgAN remains insufficiently explored. In this study, serum exosomes were isolated from patients with progressive or non-progressive IgAN and healthy controls. tsRNA expression profiles were obtained using small RNA sequencing and validated by qRT-PCR. Bioinformatic analyses were conducted to identify target pathways. Functional effects of candidate tsRNAs were evaluated using luciferase reporter assays, tsRNA mimic/antago transfections, and co-culture of B cell-derived exosomes with collecting duct epithelial cells (CDECs). Among 566 identified exosomal tsRNAs, tRNA-Pro-TGG was significantly upregulated in patients with progressive IgAN. It was enriched in B lymphocytes and correlated with serum soluble TNFR1 levels. Functional assays revealed that exosomal tRNA-Pro-TGG suppressed MAPK translation and activated proinflammatory responses in CDECs, including increased secretion of TNF-α, IL-6, and CCL2. ROC analysis demonstrated its robust diagnostic power for distinguishing progressive from non-progressive disease (AUC = 0.9618). This study identifies exosomal tRNA-Pro-TGG as a novel, non-invasive biomarker for IgAN progression and implicates it as a mediator of immune-driven renal inflammation. These findings offer valuable insights into IgAN pathogenesis and support the potential clinical utility of tsRNA-based diagnostics in nephrology.