Using network pharmacology to discover potential drugs for hypertrophic scars

BACKGROUND: Hypertrophic scarring is a disease of abnormal skin fibrosis caused by excessive fibroblast proliferation. Existing drugs have not achieved satisfactory therapeutic effects. OBJECTIVES: To explore the molecular pathogenesis of hypertrophic scars and screen effective drugs for their treatment. METHODS: Existing human hypertrophic scar RNA sequencing data were utilized to search for hypertrophic scar-related gene modules and key genes through weighted gene co-expression network analysis (WGCNA). Candidate compounds were screened in a compound library. Potential drugs were screened by molecular docking and verified in human hypertrophic scar fibroblasts and a mouse mechanical force hypertrophic scar model. RESULTS: WGCNA showed that hypertrophic scar-associated gene modules influence focal adhesion, the transforming growth factor (TGF)-β signalling pathway and other biologic pathways. Integrin β1 (ITGB1) is the hub protein. Among the candidate compounds obtained by computer virtual screening and molecular docking, crizotinib, sorafenib and SU11274 can inhibit the proliferation and migration of human hypertrophic scar fibroblasts and profibrotic gene expression. Crizotinib had the best effect on hypertrophic scar attenuation in mouse models. At the same time, mouse ITGB1 small interfering RNA can also inhibit mouse scar hyperplasia. CONCLUSIONS: ITGB1 and TGF-β signalling pathways are important for hypertrophic scar formation. Crizotinib could be a potential treatment drug for hypertrophic scars.