Circulating non-canonical small noncoding RNAs as novel diagnostic biomarkers for tuberculosis

Tuberculosis (TB) persists as a formidable global health challenge, largely due to limitations in current diagnostic methodologies that hinder early and accurate detection. To address this critical unmet need, we conducted a translational investigation into serum-derived non-classical small noncoding RNAs (tsRNAs, rsRNAs, and snoRNAs) as next-generation liquid biopsy biomarkers. Serum samples were collected from a well-defined cohort of confirmed TB patients and matched healthy controls (HCs) and their sncRNA content was comprehensively profiled via high-throughput small RNA sequencing with molecular barcoding. Differential expression analyses revealed a distinct panel of three non-canonical sncRNAs that were significantly upregulated in TB patients compared to controls. The diagnostic robustness of this tripartite RNA signature was rigorously validated across two independent multi-center cohorts (Cohort 1: TB=41, HC=37; Cohort 2: TB=71, HC=70), achieving exceptional discrimination power with AUCs of 0.97 and 0.94 respectively. Our findings unveil a novel serum sncRNA signature may serve as a highly sensitive and specific biomarker for the diagnosis of tuberculosis, thereby enabling rapid therapeutic initiation and precision public health interventions.