Integrated Network Pharmacology and Molecular Docking to understand the Mechanisms of Methotrexate-induced Intestinal Toxicity

Methotrexate, a versatile therapeutic agent, is associated with significant intestinal toxicity, posing clinical challenges. To comprehensively elucidate the underlying mechanisms, we employed an integrated approach combining network pharmacology and molecular docking. Our study identified 155 common targets associated with methotrexate and intestinal toxicity. Network analysis unveiled pivotal nodes, highlighting the TNF signaling pathway and PI3K-AKT signaling pathway. Gene ontology and KEGG pathway enrichment analysis revealed associations with inflammation, apoptosis and immune responses. The constructed D-C-T-P-D network illuminated complex interactions between methotrexate, target genes, pathways and diseases, emphasizing key targets including TNF, AKT1, CASP3 and others. Molecular docking simulations demonstrated robust binding affinities between methotrexate and these targets. AKT1 and CASP3 exhibited the strongest interactions, suggesting their pivotal roles in methotrexate-induced intestinal damage. Our findings provide insights into the molecular basis of this adverse effect, offering potential therapeutic targets for intervention. However, further experimental validation and consideration of individual patient factors are warranted to translate these discoveries into clinical practice. This underscores the need for personalized approaches to mitigate methotrexate-induced intestinal toxicity.