Mechanistically, ADAMTS2 knockdown attenuated PI3K/AKT/mTOR phosphorylation, and these protective effects were partially reversed by the PI3K agonist 740 Y-P.<h4>Conclusion</h4>ADAMTS2 knockdown mitigated LPS-induced epithelial injury and barrier dysfunction, in association with PI3K/AKT/mTOR signaling and autophagy-related changes, suggesting ADAMTS2 as a potential therapeutic target for ARDS pending further in vivo validation. Here, ADAMTS2 is linked to acute respiratory distress syndrome.