Sodium Danshensu promotes diabetic wound healing by targeting the EGFR-mediated PI3K-AKT pathway: a combined network pharmacology, machine learning, and in vitro approach

Abstract

Sodium Danshensu (SDSS) shows potential in treating diabetic wounds (DWs) owing to its antioxidant, anti-inflammatory, and pro-angiogenesis effects. The specific pharmacological mechanisms of SDSS in achieving the above effects were evaluated. The potential targets of SDSS and DWs were obtained from online databases. Interaction networks were constructed using network pharmacology, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Combined with machine learning, the biological targets were evaluated and prioritized. A high-glucose-induced human umbilical vein endothelial cell (HUVEC) model was established for in vitro studies. A total of 126 shared targets of SDSS and DWs were selected, and the core targets included EGFR, CASP3, SRC, ESR1, JUN, NFKB1, IGF1R, ESR2, AR, and PPARG. KEGG enrichment analysis revealed significant enrichment of the PI3K-AKT signaling pathway (P < 0.05). Machine learning indicated EGFR as a key target of SDSS in treating DWs. Findings from molecular docking and molecular dynamics simulation confirmed the stable combination of SDSS and EGFR. In vitro experiments indicated that SDSS may activate the PI3K-AKT pathway via EGFR targets, improve the mobility of high-glucose-induced HUVECs, and increase lumen formation (branch number). It promoted catalase production and inhibited the release of malondialdehyde and inflammatory factors including tumor necrosis factor-α and interleukin-6 (all P < 0.05). SDSS activates the PI3K-AKT pathway via EGFR, promotes endothelial cell migration and angiogenesis, and inhibits oxidative stress and the inflammatory response, highlighting its potential in treating DWs.