Unraveling the Mechanisms of Madecassoside Derivatives in Wound Healing: Network Pharmacology and Experimental Validation

<b>Background:</b> Madecassoside is widely utilized in wound healing due to its multiple physiological activities. However, its limited bioavailability and solubility hinder its clinical application. Enzymatic hydrolysis has been employed to enhance the bioavailability and bioactivity of natural products, but its potential for modifying madecassoside remains unexplored. <b>Methods:</b> In this study, we prepared MA1G and MA2G through enzymatic hydrolysis, inspired by the metabolic processes of madecassoside. Network pharmacology was employed to investigate the mechanisms of these madecassoside derivatives (MDs) in wound healing, and molecular docking was performed to evaluate their binding affinities. Transdermal permeation studies, scratch assays, and antioxidant and anti-inflammatory tests were conducted to characterize the biological properties and activities of MDs. <b>Results:</b> Network pharmacology identified TLR4, NF-κB, and STAT3 as key targets for wound healing, and the MDs inhibited the expression of these proteins in vitro. Additionally, the results demonstrated that MDs exhibited robust reactive oxygen species (ROS) scavenging activity (43.05-147.50% reduction) and significantly enhanced cell migration (36.76-77.28% increase). Notably, the biomodified MA2G showed superior transdermal permeability and biological activities. <b>Conclusions:</b> This paper represents the first report directly comparing the biological activities of the parent compound (madecassoside) and its metabolites while simultaneously proposing a novel therapeutic strategy for wound healing.