Integrating Network Pharmacology and Experimental Verification to Explore the Targets for Colchicine against Coronary In-Stent Restenosis.

INTRODUCTION

In-Stent Restenosis (ISR) remains a challenging complication following vascular interventions. Colchicine, a well-known anti-inflammatory agent, has shown potential in reducing ISR, but its multi-target mechanisms remain unclear. This study aims to elucidate the pharmacological mechanisms of colchicine against ISR using an integrated approach.

METHODS

Colchicine- and ISR-related targets were identified from multiple public databases. Overlapping targets were analyzed using Gene Ontology (GO), KEGG pathways, and Protein-Protein Interaction (PPI) networks. Hub genes were identified using the MCODE and CytoHubba algorithms and subjected to Reactome enrichment analysis. Molecular docking assessed colchicine's binding affinity to hub proteins. A rat carotid artery balloon injury model was used to evaluate colchicine's therapeutic effect, focusing on histological and molecular changes.

RESULTS

A total of 30 overlapping targets were identified, primarily enriched in atherosclerosis-related and inflammatory signaling pathways. Three key targets, including TGF-β1, ICAM1, and VCAM1, were identified as central to extracellular matrix organization and inflammatory pathways. Molecular docking revealed strong binding affinity between colchicine and these targets (binding energy < -5 kcal/mol). In vivo, colchicine significantly attenuated neointimal hyperplasia, reduced collagen deposition, and downregulated the expression of TGF-β1, ICAM1, and VCAM1 at both mRNA and protein levels.

DISCUSSION: Our findings suggest that colchicine suppresses ISR by simultaneously modulating inflammatory and fibrotic processes. The identification of TGF-β1, ICAM1, and VCAM1 as hub targets underscores their roles in neointimal development and highlights colchicine's potential to regulate multiple pathological pathways. Compared with conventional drug-eluting stent agents that primarily inhibit smooth muscle cell proliferation, colchicine offers complementary advantages through dual anti-inflammatory and anti-fibrotic mechanisms. Nonetheless, further studies are warranted to optimize drug delivery strategies, explore dose-response relationships, and compare colchicine with standard stent-based therapies.

CONCLUSION

Colchicine may exert anti-restenotic effects by suppressing inflammatory and fibrotic mediators such as TGF-β1, ICAM1, and VCAM1. These findings suggest a possible multi-target mechanism and support further investigation into its therapeutic potential in ISR.