BACKGROUND: Acute lung injury (ALI) is a serious respiratory ailment marked by dysregulation of the immune dysregulation and an inflammatory reaction.Currently, effective treatment options for ALI are limited. Sanzi Yangqin Decoction (SZYQ) is a traditional formula used clinically to treat respiratory diseases, although its effects on ALI have not yet been fully elucidated. PURPOSE: This research seeks to elucidate the pharmacodynamic material basis of SZYQ within the context of lipopolysaccharide (LPS)-induced ALI, thereby establishing a robust foundation for considering SZYQ as a possible intervention for improving ALI. METHODS: The chemical constituents of SZYQ were identified by UHPLC-QTOF-MS. The pharmacological mechanism of SZYQ on ALI was preliminarily investigated through network pharmacology. An ALI model induced by LPS was employed to evaluate the efficacy of SZYQ via histopathological analysis and other methodologies. Transcriptomic analysis of lung tissue from ALI mice was conducted to uncover the potential mechanisms underlying SZYQ's effects. Additionally, LPS was used to induce murine alveolar macrophages (MH-S), creating an in vitro ALI model
siRNA was introduced to further validate the pharmacological mechanisms of SZYQ's protective effects on ALI. RESULTS: This study identified a total of 37 chemical components within SZYQ, and network pharmacology results indicated that these components exert their effects via the Toll-like receptor pathway. The protective effects of SZYQ on ALI are manifested by the modulation of the immune response and the reduction of lung epithelial barrier damage. Transcriptomics, western blot, flow cytometry, and siRNA experiments demonstrated that SZYQ can inhibit levels of TLR2, p-NF-κB/NF-κB, p-IκB/IκB, p-IKKα/IKKα, MyD88, NLRP3, Caspase-1 and ASC. Furthermore, SZYQ was observed to reduce the release of reactive oxygen species (ROS), suppresses inflammasome activation, as well as decrease the incidence of cell pyroptosis. CONCLUSIONS: This article demonstrated for the first time that SZYQ can enhance ALI through immune regulation. The proposed mechanism of action involved the TLR2-mediated NF-κB/NLRP3 signaling pathway and the inhibition of NLRP3 inflammasome activation.