Unveiling Active Natural Products for the Therapy of Inflammatory Bowel Disease through Single-cell, Transcriptome, and Reverse Network Pharmacology

Introduction: Inflammatory bowel disease (IBD) poses a major threat to human health. Current pharmacological therapies primarily manage symptoms and are often associated with adverse effects. Objective: To develop targeted natural drugs with fewer side effects for IBD therapy by identifying potential agents from medicinal and edible Chinese herbs (MECHs) and clarifying their underlying molecular mechanisms. Methods: An integrated approach was employed, combining single-cell analysis, transcriptomics, reverse network pharmacology, immunological infiltration assessment, molecular docking, ADMET evaluation, and molecular dynamics (MD) simulations. Results: Multi-omic integration identified nine differentially infiltrating immune cell types and a CXCL8-CXCR2-driven neutrophil communication axis. Frequent intercellular communication was observed among neutrophils, epithelial cells, monocytes, B cells, and T cells. Topological screening yielded 15 hub targets and identified MMP2 and PTGS2 as key targets. Molecular docking, ADMET analyses, and 100-ns MD simulations converged on the natural product (NP) MOL009551 (isoprincepin) as a high-affinity, stable MMP2 binder (ΔG = -11.0 kcal/mol), supporting MMP2-directed isoprincepin as a novel therapeutic candidate for IBD. Discussion: Bioinformatic analyses suggest that MMP2 may play an important role in IBD, and isoprincepin, identified from MECHs, may serve as a potential therapeutic agent by modulating MMP2 activity. However, experimental validation of their direct interaction and therapeutic efficacy remains necessary, along with further mechanistic and preclinical studies to clarify their potential for IBD treatment. Discussion: Bioinformatic analyses suggest that MMP2 may play an important role in IBD, and isoprincepin, identified from MECHs, may serve as a potential therapeutic agent by modulating MMP2 activity. However, experimental validation of their direct interaction and therapeutic efficacy remains necessary, along with further mechanistic and preclinical studies to clarify their potential for IBD treatment. Conclusion: This study provides a comprehensive understanding of the molecular mechanisms underlying IBD, identifies MMP2 as a key target, and highlights isoprincepin as a promising natural product for IBD therapy.