ITGA5 accelerates diabetic wound healing by alleviating endothelial mitochondrial iron overload and promoting mitocytosis

Diabetic foot ulcer (DFU) is a severe complication characterized by impaired angiogenesis and persistent endothelial dysfunction associated with mitochondrial dysfunction. This study investigated Integrin subunit alpha 5 (ITGA5) as a regulator of endothelial mitochondrial quality control and wound repair under diabetic conditions. ITGA5 expression was analyzed in clinical DFU tissues and normal skin tissues. The effects of lentiviral ITGA5 overexpression were evaluated in a db/db diabetic mouse wound model, and gain- and loss-of-function experiments were performed in high glucose-treated endothelial cells. Mannitol was used as an osmotic control. Mechanisms involving PI3K/AKT signaling, iron metabolism, and KIF5B-dependent mitochondrial transport to migrasomes were investigated using pathway inhibition and knockdown approaches. ITGA5 was significantly downregulated in clinical DFU tissues. In diabetic mice, ITGA5 overexpression accelerated wound closure, improved collagen organization, enhanced angiogenesis, and increased ITGA5/CD31-positive vascular signals. In vitro, ITGA5 restoration improved endothelial cell viability, migration, and tube formation, whereas ITGA5 knockdown aggravated high glucose-induced endothelial dysfunction, mitochondrial ROS accumulation, and iron overload. Mechanistically, ITGA5 activated the PI3K/AKT pathway, reduced mitochondrial iron accumulation and lipid peroxidation, and regulated iron metabolism-related proteins, including TfR1, FPN1, and Ferritin. Inhibition of PI3K/AKT signaling pathway partially reversed these effects. Furthermore, ITGA5 promoted KIF5B-dependent mitocytosis, facilitating migrasome-mediated expulsion of damaged mitochondria, while KIF5B knockdown weakened ITGA5-mediated mitochondrial protection. ITGA5 facilitates diabetic wound healing by preserving endothelial mitochondrial function through PI3K/AKT-mediated regulation of iron homeostasis and KIF5B-dependent mitochondrial export via migrasomes, highlighting its potential as a therapeutic target for DFU.