Mechanistic Insights into Maxing Shigan Decoction in Community-Acquired Pneumonia Based on Bioinformatics and Experimental Validation.

PURPOSE: To explore the mechanisms of Maxing Shigan Decoction (MXSGD) in community-acquired pneumonia (CAP) via network pharmacology, machine learning, molecular docking, and experimental validation. METHODS: MXSGD active compounds and targets were collected from TCMSP and TCM-ID; CAP-related genes were obtained from GEO datasets, and integrated with targets from GeneCards, OMIM, DisGeNET, and TTD. Overlapping targets were subjected to PPI, GO, and KEGG analyses. LASSO and SVM-RFE were used to select feature genes, and six core targets with robust diagnostic performance (AUC > 0.8 in both training and validation sets) were identified after ROC evaluation. Immune infiltration, GSEA, molecular docking, and 100 ns molecular dynamics simulations were performed. In vivo, the efficacy of MXSGD was assessed in a clinically relevant influenza A virus-Streptococcus pneumoniae co-infection mouse model by measuring lung index, histopathology, serum IL-6 and TNF-α levels by ELISA, and mRNA expression by qRT-PCR. RESULTS: We obtained 139 active compounds, 867 MXSGD targets, and 4,444 CAP genes, yielding 262 shared targets enriched in immune-inflammation pathways. Six core targets with high diagnostic accuracy were identified: ABCB1 (AUC = 0.9072), KIT (AUC = 0.8072), PLA2G7 (AUC = 0.8391), SLC2A3 (AUC = 0.9372), PRF1 (AUC = 0.8082), and GPR18 (AUC = 0.8414). Immune infiltration revealed eight differentially abundant immune cell types. Molecular docking and molecular dynamics supported the stable binding of glabridin to KIT and SLC2A3. In vivo, MXSGD significantly ameliorated lung pathological injury, reduced lung index and serum IL-6 and TNF-α levels (FDR-adjusted P < 0.001), and partially reversed mRNA expression changes of KIT, GPR18, and SLC2A3 (FDR-adjusted P < 0.05), while changes in ABCB1, PLA2G7, and PRF1 showed a trend without statistical significance. CONCLUSION: These results suggest that MXSGD may exert immunomodulatory and anti-inflammatory effects in CAP, potentially by regulating ABCB1, KIT, PLA2G7, SLC2A3, PRF1, and GPR18; however, only three of these (KIT, GPR18, and SLC2A3) showed statistically significant mRNA changes. These findings provide a multi-component, multi-target rationale requiring further experimental and clinical confirmation.