Integrating Untargeted Metabolomics Revealed Ferulic Acid Treatment on Endothelial Progenitor Cells Mediated Vascular Dysfunction Following Diabetic Wound

ABSTRACT Vascular regeneration dysfunction is key to the difficulty of healing diabetic wounds. Ferulic acid (FA) has been reported to be crucial in vascular regeneration. This work aimed to investigate the mechanism of FA in treating vascular regeneration dysfunction in diabetes. We investigated the impact of FA on wound healing and angiogenesis in diabetic rat wounds by injecting streptozotocin (STZ) into rats and excising full‐thickness skin from the rats' backs. The effects of FA on the viability, migration, and angiogenesis of endothelial progenitor cells (EPCs) induced by high glucose (HG) were studied. Molecular docking and DARTS analysis of FA and HYAL1 were conducted. Knockdown and overexpression were utilized to investigate the regulatory mechanism of FA on diabetic angiogenesis. Metabolomics research was carried out to examine the regulation of serum metabolites by FA. The results showed that Intervention with FA resulted in smaller wounds in rats compared to the non‐intervention group. The newly formed epidermis in rats after FA intervention was thicker, and the re‐epithelialization rate and collagen deposition rate were higher. FA intervention increased the number of circulating EPCs in the peripheral blood of diabetic rats and enhanced the cellular activity, migration, and tube‐forming capacity of bone marrow (BM)‐EPCs. Upregulation of HYAL1 expression reduced the level of MMP‐9, decreased the cell activity of BM‐EPCs, and weakened the adhesion, migration, and vascular formation ability of BM‐EPCs. Molecular docking and DARTS results showed that FA could bind to HYAL1 protein. HG intervention elevated the level of HYAL1, and FA intervention reversed the effect of HG intervention. FA intervention could regulate the metabolism of rats with diabetic wounds. In conclusion, FA enhanced the wound healing process and promoted vascular genesis in diabetic rats by suppressing HYAL1 and enhancing the function of BM‐EPCs in diabetes.