<i>Moutan Cortex</i> Extract Mediates Diabetic Retinopathy by Blocking the ROS‑Triggered HIF‐1α/VEGF Axis in Retinal Pigment Epithelial Cells

ABSTRACT Moutan Cortex is a functional food ingredient with multiple health benefits, but its effects on diabetic retinopathy (DR) remain unexplored. This study elucidates the protective roles and mechanistic insights of Moutan Cortex extract (MCE, 50% ethanol) against DR using streptozotocin‐induced diabetic rats and human retinal pigment epithelial (ARPE‐19) cells challenged with high glucose. Daily gavage of 100, 200, and 400 mg/kg MCE over 8 week dose‐dependently preserved retinal structure in diabetic rats (all p &lt; 0.05). Network pharmacology predicted the hypoxia‐inducible factor 1‐alpha/vascular endothelial growth factor (HIF‐1α/VEGF) axis as a critical pathway. Accordingly, MCE reduced HIF‐1α and VEGF protein levels in both rat retina and ARPE‐19 cells under hyperglycemia. In wound healing assays using conditioned medium from MCE‐treated ARPE‐19 cells (100, 200, and 400 μg/mL), endothelial cell migration at 24 h was reduced to 45.4%, 37.0%, and 26.4%, respectively, indicating a paracrine anti‐angiogenic effect. MCE also significantly alleviated reactive oxygen species (ROS) overproduction. Notably, H 2 O 2 or the HIF‐1α agonist CoCl 2 both reversed the inhibitory effect of MCE (400 μg/mL) on high‐glucose‐mediated HIF‐1α and VEGF overexpression. These findings indicate that MCE alleviates DR progression, partly by paracrine‐mediated anti‐angiogenesis, suppressing the HIF‐1α/VEGF axis through ROS reduction in retinal pigment epithelium (RPE) cells.