tiRNA-Pro-AGG-001 serves as a host-directed prognostic biomarker and therapeutical target for pediatric sepsis.

Pediatric sepsis and septic shock remain major causes of mortality in Children, yet robust, mechanistically anchored biomarkers for severity stratification are limited. We profiled plasma tRNA-derived small RNAs (tsRNAs) in children with sepsis and septic shock, and validated candidates by qRT-PCR in an expanded cohort. tiRNA-Pro-AGG-001 showed a stepwise decline from controls to sepsis and septic shock. In cecal ligation and puncture (CLP) mice, tiRNA-Pro-AGG-001 decreased in plasma and major organs.Prophylactic administration of tiRNA-Pro-AGG-001 agomir prior to CLP improved survival, attenuated lung/liver/kidney injury, and reduced IL-1β, IL-6 and TNF-α responses, whereas antagomir silencing worsened outcomes in a non-severe CLP setting. Mechanistically, tiRNA-Pro-AGG-001 targeted Notch1 mRNA, suppressed Notch1/NF-κB activation, and restrained an M1-like macrophage program across macrophage models. These findings define a tiRNA-Pro-AGG-001-Notch1/NF-κB axis linking tsRNA dysregulation to inflammatory amplification and organ injury, supporting an association between tiRNA-Pro-AGG-001 and disease severity and suggesting its prophylactic intervention as a promising strategy, with future therapeutic-window studies needed to establish its translational potential for pediatric sepsis.