Revealing the Mechanisms of Shikonin Against Diabetic Wounds: A Combined Network Pharmacology and In Vitro Investigation.

Background: Shikonin (SHK) possesses extensive pharmacological effects including antimicrobial and anti-inflammatory properties for diabetic wound (DW), while its molecular mechanism remains to be clarified. In this study, we investigated the potential mechanisms of SHK in treating DW by combining network pharmacology and in vitro experiments. Methods: We obtained potential targets for SHK and DW from the publicly available database. Based on the interaction network and conducting GO and KEGG pathway enrichment analysis, we constructed a target pathway network to explore the relationship between SHK and DW. To validate the mechanism of SHK, we established an in vitro experimental model. Results: Sixty intersecting targets between SHK and DW were obtained, and the top 10 targets of the protein-protein interaction (PPI) network included AKT1, SRC, EGFR, CASP3, MMP9, PPARG, ESR1, ANXA5, MMP2, and JAK2. Based on target-pathway networks, the PI3K-AKT signaling pathway was found to be a signaling pathway with low p value in enrichment analysis. In vitro experiments revealed that SHK significantly promoted angiogenesis. Meanwhile, SHK could inhibit the high glucose-induced human umbilical vein endothelial cell dysfunction through regulating the PI3K-AKT pathway. Conclusion: This study initially revealed the molecular mechanism of SHK in DW by multitarget and multipathway. The PI3K-AKT signaling pathway, MAPK signaling pathway, and AGE-RAGE signaling pathways may be the main pathways of SHK in treating DW.