tRF‐5004b Enriched Secretory Autophagosomes Induce Endothelial Cell Activation to Drive Acute Respiratory Distress Syndrome

Abstract Acute respiratory distress syndrome (ARDS) is an acute inflammatory lung injury for which effective therapeutic agents are lacking. Excessive endothelial cell (EC) activation is a critical trigger of inflammation. Extracellular vesicles (EVs) are increasingly recognized as prominent regulators of inflammatory responses. The previous study identified secretory autophagosomes (SAPs), a novel class of EVs, as a prognostic marker in ARDS, raising questions of whether and how they are involved in the pathogenesis of ARDS. Here, it is shown that inflamed macrophage‐derived SAPs (MSAPs) exacerbate lung injury by weakening the role of ECs as gatekeepers of immune cell transport within the lung. Bioinformatics and functional studies reveal that tRF‐5004b is a key molecule of MSAPs in mediating endothelial activation. Mechanically, tRF‐5004b directly interacts with the nuclear transporter KPNA2, thereby facilitating the association between KPNA2 and the transcription factor p65. This interaction enhances p65 nuclear translocation, a process implicated in EC activation. Additionally, the level of tRF‐5004b is positively correlated with the severity of ARDS, and patients with high tRF‐5004b levels have a poor prognosis. Overall, it is found that tRF‐5004b‐enriched SAPs induce acute lung injury by promoting p65 nuclear translocation to activate ECs, suggesting that tRF‐5004b may be a novel therapeutic target for ARDS.