Quercetin attenuates high glucose-induced VEGFA expression in ARPE-19 cells by inhibiting ROS generation, p38 MAPK...

Hyperglycemia-driven oxidative stress and inflammatory signaling in retinal pigment epithelium (RPE) promote overexpression of vascular endothelial growth factor A (VEGFA), contributing to the pathogenesis of diabetic retinopathy (DR). Quercetin, a dietary flavonoid with antioxidant and anti-inflammatory properties, has not been fully evaluated for its ability to counteract high glucose–induced VEGFA upregulation in RPE. Here, ARPE-19 cells were exposed to high glucose (30 mM) with or without quercetin (5 or 20 µM) treatment. VEGFA expression was measured by qPCR and ELISA; intracellular reactive oxygen species (ROS) were assessed using a DCFH-DA probe; and pathway activation was examined by immunoblotting for p38 MAPK and ERK1/2 phosphorylation, IκBα stability, and NF-κB p65 nuclear translocation. N-acetylcysteine (NAC) served as an antioxidant control, and cell viability was monitored using the CCK-8 assay. Quercetin at non-cytotoxic concentrations significantly suppressed high glucose–induced VEGFA mRNA and protein expression, reduced ROS accumulation, and attenuated p38 MAPK phosphorylation without altering ERK1/2 activation. Quercetin also prevented IκBα degradation and diminished p65 nuclear translocation, indicating inhibition of NF-κB signaling. These findings support a model in which quercetin mitigates hyperglycemia-induced VEGFA upregulation in RPE cells at least in part by modulating a ROS–p38 MAPK–NF-κB axis, while not excluding contributions from other glucose- and ROS-sensitive pathways. Quercetin may therefore represent a readily accessible adjunctive strategy to address oxidative stress, inflammation, and VEGFA dysregulation in DR, warranting further in vivo validation.