Isovitexin accelerates diabetic wound repair via coordinated angiogenesis and collagen remodeling: Mechanistic insights from cellular and streptozotocin-induced SD rat models

Chronic diabetic wounds pose significant clinical challenges due to persistent inflammation, vascular insufficiency, and impaired tissue remodeling, leading to poor healing outcomes. The PI3K/Akt/eNOS signaling pathway is critical for regulating angiogenesis, apoptosis, and extracellular matrix organization—key processes disrupted in diabetic wounds. Isovitexin, a natural flavonoid from plants like passionflower and Cannabis, exhibits well-documented antioxidant and anti-inflammatory properties. However, its therapeutic potential and mechanistic action in diabetic wounds, particularly regarding multi-targeted regulation of angiogenesis, collagen deposition, and apoptosis within the complex wound microenvironment, remain unexplored. This study demonstrates that isovitexin accelerates diabetic wound healing. Using streptozotocin-induced diabetic rodent models and cell culture, we found isovitexin significantly promoted angiogenesis and vascular maturation, reduced oxidative damage and apoptosis, and improved collagen organization versus controls. Crucially, these effects were entirely abolished by the eNOS inhibitor L-NAME, confirming PI3K/Akt/eNOS pathway specificity. Whereas previous studies have largely focused on single-pathway interventions for diabetic wounds, the concurrent modulation of angiogenesis, matrix remodeling, and apoptosis remains unexplored. Our study uniquely demonstrates that isovitexin activates the PI3K/Akt/eNOS pathway to synchronously enhance angiogenesis, promote collagen maturation, and inhibit apoptosis. This tripartite mechanism—uncovered for the first time—provides a novel therapeutic strategy to address the multifactorial pathology of diabetic wounds. Future research should prioritize clinical translation of these findings.