Bu Zhong Yi Qi Tang targets key monocyte-associated genes to enhance sepsis therapy

ETHNOPHARMACOLOGICAL RELEVANCE: Sepsis is a life-threatening condition resulting from an uncontrolled immune response to infection, leading to organ dysfunction and severe complications. Bu Zhong Yi Qi Tang (BZYQT), a traditional Chinese medicinal formulation, has been recognized for its diverse pharmacological effects, particularly in modulating immune responses and alleviating inflammation. However, the specific role and mechanism of BZYQT in the adjunctive treatment of sepsis are still unclear. AIM OF THE STUDY: To investigate the role and underlying mechanisms of BZYQT in the adjunctive therapy of sepsis. MATERIALS AND METHODS: scRNA-seq was employed to analyze PBMCs from patients with sepsis and healthy controls, identifying cell populations and functional states. Pseudotime and cell-cell communication analyses were conducted to investigate the origins and interactions of Sep_monocytes. hdWGCNA and machine learning techniques were utilized to identify key genes. The adjuvant therapeutic efficacy of BZYQT was assessed in a cecal ligation and puncture (CLP) mouse model, as well as in clinical trials. RESULTS: Seven populations of PBMCs and twelve subclusters of monocytes were identified, with two subclusters (Sep_monocytes) enriched in sepsis patients. Furthermore, critical gene modules were identified, with METTL9, SAT1, and SRGN being pinpointed as potential sepsis biomarkers. Notably, BZYQT was found to target these genes, modulating their expression. In the CLP mouse model, BZYQT administration (0.2 ml/10 g/d) in combination with imipenem/cilastatin (50 mg/kg/d) led to improved survival rates, significantly reduced bacterial loads, diminished inflammation, and enhanced antibacterial effects. Clinically, BZYQT alleviated symptoms, modulated immune cells, and reduced inflammatory markers, underscoring its potential efficacy as an adjunctive therapy for sepsis. CONCLUSION: BZYQT enhances sepsis therapy by targeting critical monocyte-associated genes, thereby modulating immune responses and reducing inflammation.