Esketamine protects against LPS-induced septic lung injury via NMDA receptor and NF-κB/NLRP3/Caspase-1/GSDMD pathway

Sepsis-induced acute lung injury (ALI) is a critical complication associated with high mortality. Esketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, has shown protective potential against organ injury; however, whether its protective effect against lung injury depends on NMDA receptor engagement remains unclear. This study investigated whether esketamine alleviates lipopolysaccharide (LPS)-induced ALI by targeting NMDA receptor subunit 2 A (NMDAR2A). In vivo, esketamine significantly reduced histopathological injury in the lungs, decreased the wet/dry (W/D) ratio, and suppressed plasma levels of inflammatory cytokines and pulmonary neutrophil extracellular trap (NETs) formation. Immunofluorescence staining showed that NMDAR2A immunoreactivity colocalized predominantly with lung macrophages, with only sparse signal detected in neutrophils or lymphocytes. In vitro experiments demonstrated that esketamine inhibited the NF-κB/NLRP3/Caspase-1/GSDMD signaling pathway and attenuated pyroptosis in RAW264.7 macrophages stimulated with LPS and ATP. The specificity of these effects was confirmed using the NMDA receptor antagonist MK-801, which mimicked the protective effects of esketamine, and the NMDA receptor agonist NMDA, which reversed them. Collectively, our results demonstrate that esketamine protects against septic ALI by inhibiting NMDAR2A-mediated macrophage pyroptosis, providing a mechanistic basis for its clinical application in sepsis management.