Hydroalcoholic gel of Angelica sinensis polysaccharides promotes wound healing by suppressing ferroptosis through PI3K/AKT/Nrf2 signaling pathway.

Abstract

BACKGROUND: Angelica sinensis polysaccharide (ASP) exhibits considerable wound-healing properties. However, its clinical application is limited by rapid evaporation in aqueous solution, which shortens its sustained action. In the early stage, we developed a gel-based formulation of ASP (ASP-G). Although ASP-G holds promise as a topical agent, its effects on wound-related ferroptosis and the underlying mechanisms remain incompletely understood. PURPOSE: This study aimed to elucidate the effects and mechanisms of ASP-G in promoting wound healing. METHODS: This study assessed the impact of ASP-G on wound healing in a mouse model of pressure ulcer (PU) in vivo, as well as in endothelial cell lines stimulated with oxygen-glucose deprivation/reoxygenation (OGD/R) or erastin in vitro. RESULTS: In vivo, ASP-G accelerated wound healing and angiogenesis and showed anti-ferroptosis effect in wound tissues. Meanwhile, key proteins in the nuclear factor erythroid 2-related factor 2 (Nrf2) pathways were upregulated following ASP-G treatment. Proteomic analysis revealed that the differentially expressed proteins were most significantly enriched in the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Western blot analysis confirmed that ASP-G treatment increased the phosphorylation levels of PI3K and AKT in wounds of PU mice. In vitro, ASP-G markedly inhibited ferroptosis induced by OGD/R in endothelial cells, enhanced p-AKT, Nrf2 and heme oxygenase-1 (HO-1) proteins expression, and improved cell migration, proliferation, and tube formation. Notably, these protective effects were abolished through either PI3K inhibition or Nrf2 knockdown. CONCLUSIONS: ASP-G promotes wound healing by suppressing ferroptosis of endothelial cells through activation of the PI3K/AKT/Nrf2 pathway.