Abstract

Acute lung injury (ALI) is a common and life-threatening critical illness with persistently high mortality, yet effective pharmacological therapies remain lacking. Norepinephrine (NE), a first-line vasopressor for septic shock, has been suggested to confer organ-protective and immunomodulatory effects in sepsis and related organ injury; however, its specific role and molecular mechanisms in ALI remain poorly defined. Here, we demonstrate both in vitro and in vivo that NE significantly attenuates ALI, and this protective effect is primarily attributable to the suppression of alveolar epithelial cell pyroptosis. Transcriptomic profiling and functional analyses reveal that NE activates the β 2 -adrenergic receptor (β 2 -AR)–cAMP/PKA signaling axis and, through the A-kinase anchoring protein AKAP1, preserves mitochondrial homeostasis, thereby interrupting the vicious cycle between mitochondrial damage and pyroptosis. Further mechanistic dissection identifies AKAP1 as an indispensable molecule for NE-mediated protection and caspase-11 as the critical downstream effector through which NE inhibits pyroptosis. Collectively, this study uncovers a novel mechanism by which NE suppresses alveolar epithelial pyroptosis and alleviates ALI via the β 2 -AR–AKAP1 axis, providing a potential therapeutic target for ALI.