Here, we demonstrated that hepatocytic GSDMD-mediated release of HMGB1 bound with the receptor for advanced glycation end products (RAGE) and subsequently promoted vascular endothelial GSDMD activation and endothelial damage in mice induced by LPS or live bacteria, resulting in systemic vascular injury, acute lung injury (ALI), and death. Here, AGER is linked to acute respiratory distress syndrome.