Abstract

Background During the healing of skin wounds, excessive fibrosis and collagen remodeling disorders often lead to the formation of proliferative scars. Fisetin is a naturally occurring flavonoid compound with antioxidant and anti-fibrotic properties. However, its therapeutic effect and mechanism of action in wound healing and inhibition of scar formation are still unknown. Methods This study used network pharmacological methods to identify potential targets and pathways related to wound healing and proliferative scar formation. Through protein-protein interaction analysis, Gene Ontology analysis and enrichment analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG), its potential biological functions were clarified. In addition, molecular docking was also carried out to evaluate the binding affinity between fisetin and the core target. The effect of fisetin on wound closure and collagen deposition was evaluated using the full-thickness skin wound model in rats. In in vitro experiments, human dermal fibroblasts were used to study the effect of fisetin on collagen expression and the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Results Network pharmacological analysis highlighted serine/threonine kinase 1 (AKT1) as a central target linking fisetin to wound repair and fibrosis. Functional enrichment indicated significant involvement of the PI3K/Akt pathway. Molecular docking further confirmed a strong binding affinity between fisetin and AKT1. In vivo experiments demonstrated that fisetin significantly accelerated wound closure, reduced inflammatory cell infiltration, and improved histological organization. Quantitative analysis showed decreased histological inflammation scores and a reduced the ratio of type I collagen (COL1A)/type III collagen (COL3A), indicating improved collagen remodeling and attenuated scar formation. Moreover, fisetin upre