We first analyzed tsRNA signatures in SLE serum and identified that tRF-His-GTG-1 was significantly upregulated in SLE serum. The combination of tRF-His-GTG-1 and anti-dsDNA could serve as biomarkers for diagnosing SLE with a high AUC of 0.95 (95% CI=0.92-0.99), sensitivity (83.72%) and specificity (94.19%). Importantly, the non-invasive serum tRF-His-GTG-1 could also be used to distinguish SLE with LN or SLE without LN with AUC of 0.81 (95% CI, 0.73–0.88) and performance (sensitivity 66.27%, specificity 96.15%). Moreover, the serum tsRNA is mainly secreted via exosome and directly target signaling molecules that play crucial roles in regulating the immune system. Overall design: We employed a strategy including the initial screening by sRNA sequencing and validation by qRT-PCR on an individual basis in 24 SLE without LN patients, 33 SLE with LN patients, and 23 healthy controls.