Vitexin Ameliorates HG‐Induced Injury in Retinal ARPE‐19 Cells by Targeting CASP3

Diabetic retinopathy (DR) stands as a common microvascular issue associated with diabetes mellitus, a condition defined by progressive structural decline in the retina. Although studies have reported that vitexin exhibits positive pharmacological activity in inflammatory eye diseases and has been shown to protect against neuronal damage, its efficacy in treating DR and its underlying mechanism of action remain unreported. Cellular viability was determined via the Cell Counting Kit‐8 (CCK‐8) approach. Oxidative stress, apoptosis, and inflammatory response in cells were assessed via flow cytometry, the thiobarbituric acid (TBA) assay, commercial kits, and western blot analysis. Combined with bioinformatics analysis (online Swiss Target Prediction, Comparative Toxicogenomics Database (CTD), online Gene Cards, and molecular docking), it was confirmed that vitexin's cytoprotection in ARPE‐19 cells against damage is mediated by caspase‐3 (CASP3). In HG‐challenged ARPE‐19 cells, vitexin successfully mitigated oxidative stress. This was evidenced by downregulated levels of malondialdehyde (MDA) and reactive oxygen species (ROS), coupled with enhanced enzymatic performance of superoxide dismutase (SOD) and glutathione peroxidase (GSH‐Px). It also attenuated the inflammatory response by suppressing tumor necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) while promoting interleukin‐10 (IL‐10), ultimately leading to reduced apoptosis. Differential gene screening and molecular docking analysis revealed an interaction between CASP3 and vitexin. Moreover, in HG challenged ARPE‐19 cells, overexpressing CASP3 significantly compromised the protective benefits conferred by vitexin. Vitexin alleviates damage to ARPE‐19 cells induced by HG via CASP3, exerting a protective effect in early DR.