Synergistic inhibition of macular vascular permeability in diabetic edema: Ginsenoside Rg3 enhances ranibizumab efficacy by targeting angiopoietin‐like protein 4 and vascular endothelial growth factor via neuropilin/RhoA signaling

ABSTRACT Aims This study investigated the molecular mechanisms by which ginsenoside Rg3 combined with ranibizumab alleviates diabetic macular edema (DME), focusing on antagonizing ANGPTL4/VEGF and regulating the NRP/RhoA pathway to reduce vascular permeability. Materials and Methods Transcriptomic sequencing compared blood samples from DME patients and healthy controls, followed by GO/KEGG enrichment analysis. In vitro, human retinal microvascular endothelial cells (HRMECs) were treated with ginsenoside Rg3 (5, 10, 20 μM) alone or combined with ranibizumab (1 mg/mL); cell viability, permeability, and protein expression were assessed. In vivo, diabetic rats received intraperitoneal ginsenoside Rg3 and ranibizumab; ocular pathology, angiogenesis, inflammation, and key protein expression/activity were evaluated. Results DME patients exhibited significant upregulation of VEGF, ANGPTL4, NRP1 (logFC = 1.9, P < 0.01), and RhoA, associated with angiogenesis/migration/inflammation pathways. In vitro, 10 μM ginsenoside Rg3 optimally reduced HRMEC permeability and suppressed ANGPTL4. Combination therapy further decreased VEGF and ANGPTL4 expression. In vivo, combined treatment significantly reduced retinal edema, angiogenesis, and vascular permeability. It markedly inhibited NRP1 expression and reduced RhoA/ROCK activity. Conclusions The combination of ginsenoside Rg3 and ranibizumab effectively antagonizes ANGPTL4 and VEGF and regulates the NRP/RhoA pathway, significantly reducing vascular permeability in DME through synergistic action. This provides crucial theoretical support for novel DME combination therapy.