Novel Applications of Metformin in the Treatment of Septic Myocardial Injury Based on Metabolomics and Network Pharmacology.

Background: While metformin has shown promise in treating septic myocardial injury (SMI), its underlying mechanisms and impact on metabolic disturbances remain poorly understood.

Methods: This study employed an integrated approach of metabolomics and network pharmacology to identify key targets and pathways through which metformin may act against SMI. Findings were validated using a lipopolysaccharide (LPS)-induced mouse model.

Results: Metformin was found to counter myocardial metabolic disruptions, indicated by the reversal of 49 metabolites primarily involved in purine metabolism, pantothenate and CoA biosynthesis, and histidine metabolism. In vivo, metformin significantly improved survival rates and cardiac function, reduced cardiomyocyte apoptosis, and inhibited inflammation and oxidative stress in LPS-induced mice. Integrated analyses identified 27 potential targets for metformin in SMI treatment. KEGG pathway analysis revealed significant enrichment in TNF, HIF-1, IL-17, and PI3K/AKT signaling pathways, while protein-protein interaction analysis pinpointed ten core targets, including IL6, IL1B, CCL2, CASP3, MMP9, HIF1A, IGF1, NOS3, MMP2, and LEP. Molecular docking and dynamics simulations demonstrated metformin's high affinity for these core targets. Further, RT-qPCR and western blot analyses confirmed that metformin modulates core target expression to mitigate SMI. Notably, our data underscore the importance of PI3K/AKT and MMP2/MMP9 signaling pathways in SMI therapy.

Conclusion: This study elucidates the metabolic and molecular mechanisms of metformin in SMI treatment, supporting its potential repurposing for SMI.