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.