Pomegranate peel extract alleviates diabetic retinopathy by suppressing the PI3K/AKT/HIF-1α/VEGF pathway and gut microbiota modulation

INTRODUCTION: Diabetic retinopathy (DR) is a severe microvascular complication of diabetes mellitus. Pomegranate peel extract (PPE) has shown potential in mitigating various diabetic complications, yet its role in DR remains unexplored. OBJECTIVE: To investigate the beneficial effects and underlying action mechanisms of PPE in managing DR. METHODS: PPE was extracted using 50 % ethanol. The effects and underlying mechanisms of PPE on DR were evaluated in streptozotocin (STZ)-induced DR rats and high-glucose-incubated adult retinal pigment epithelial cell line (ARPE-19) cells. Phenotypic parameters, network pharmacology (NP), and gut microbiota metagenomic analysis were employed to elucidate the impact and mechanisms of PPE in DR. RESULTS: In DR rats, oral administration of PPE significantly mitigated retinal damage. NP analysis indicated potential mechanisms, involving the hypoxia-inducible factor-1/vascular endothelial growth factor (HIF-1/VEGF), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), and reactive oxygen species (ROS) pathways. PPE suppressed oxidative stress and inhibited the activation of PI3K/AKT/HIF-1α/VEGF pathway in the retina of DR rats and high-glucose-incubated ARPE-19 cells. Moreover, PPE improved gut microbiota dysbiosis in DR rats, particularly increasing Akkermansia muciniphila, which likely contributed to reduced inflammation and oxidative stress. CONCLUSION: PPE exhibited therapeutic effects in DR by directly alleviating retinal damage via the suppression of oxidative stress and inhibition of PI3K/AKT/HIF-1α/VEGF pathway, as well as indirectly modulating gut microbiota. These findings suggested that PPE may serve as a promising nutraceutical for DR management.