Herein, we observed that increased MDA content and reduced SOD and GSH-Px activities in ALI mice were reversed by Poldip2 knockdown, suggesting that knockdown of Poldip2 protects mice against accelerated LPS-induced oxidative stress via enhancing antioxidant enzymes expression and inhibiting lipid peroxidation. Here, POLDIP2 is linked to acute respiratory distress syndrome.