Ze-qi Decoction Inhibits Neutrophil Extracellular Trap Formation to Suppress the Progression and Metastasis of Non-Small Cell Lung Cancer

Non-small-cell lung cancer (NSCLC) research has focused on complementary and well-established treatments with clear mechanisms and less toxicity. Immune dysregulation is vital in NSCLC progression and metastasis. Ze-qi decoction (ZQD) exhibits therapeutic effects in patients with NSCLC; however, its pharmacodynamic material basis and specific mechanisms remain unclear. In this study, we integrated UPLC-HRMS, pharmacological analysis, and transcriptomic analysis to identify the potential effective components of ZQD and elucidate its intrinsic mechanisms. ZQD exhibited potent anti-NSCLC activity in the mouse subcutaneous tumor model. A total of 297 bioactive compounds were identified in mouse plasma following ZQD administration. Pharmacological analysis revealed liquiritigenin, vibsanin B, and 11-keto-beta-boswellic acid as the potential active ingredients of ZQD and suggested that ZQD exerted anti-NSCLC effects primarily via immunomodulatory and anti-inflammatory pathways. Integrative analysis of network pharmacology and transcriptomics indicated the neutrophil extracellular trap (NET) formation as a key pathway. Further analysis showed that ZQD disrupted the neutrophil recruitment environment by decreasing hypoxia-inducible factor-1α, CD18, and intercellular adhesion molecule-1 levels and downregulating NET-related markers (citrullinated histone H3, myeloperoxidase, and neutrophil elastase). Finally, these results were confirmed in a lung metastasis model. This is the first study designed to analyze the material basis of ZQD responsible for its effect on NSCLC. Our results indicate that the mechanisms of action of ZQD involve impeding neutrophil recruitment and activation, as well as reducing the levels of NETs-related markers. These suggest the potential of ZQD in suppressing NETs formation or release, inhibiting NSCLC progression and metastasis.