Daidzein protected against sepsis-induced acute lung injury by suppressing pyroptosis via activation of estrogen receptor-β.

Sepsis-induced acute lung injury (SI-ALI) carries an extremely high mortality rate. Daidzein is a natural phytoestrogen with anti-inflammatory properties. Estrogen receptor β (ERβ) is a potential target for inflammatory regulation. However, whether Daidzein protects against cecal ligation and puncture (CLP)-induced ALI by targeting ERβ remains unclear. In this study, we established SI-ALI models in vivo and in vitro, and employed transcriptomics, metabolomics, molecular docking, dynamics simulation and pharmacological intervention. We found that Daidzein markedly alleviated CLP-induced ALI. Daidzein exhibited strong binding to ERβ, while ERβ antagonists abrogated its protective effects. Transcriptomic, metabolomics and biochemical analyses confirmed Daidzein inhibited the NLRP3/Caspase-1/Gasdermin-D pyroptosis pathway and arachidonic acid is a metabolite. Collectively, Daidzein targets ERβ to suppress macrophage pyroptosis and inflammation through the NLRP3 inflammasome pathway, thereby ameliorating sepsis-induced ALI. These findings highlight a promising therapeutic strategy for ALI treatment.