GPR30-driven fatty acid oxidation targeted by ginsenoside Rd maintains mitochondrial redox homeostasis to restore vascular barrier in diabetic retinopathy

• DOI: 10.1186/s12933-025-02638-3
• Publication Date: 2025-03-14T13:17:11Z
• Authors: Kai Tang; Congcong Huang; Zhengjie Huang; Zhen Wang; Ninghua Tan
• Keywords: Angiology; Homeostasis

Blood-retinal barrier (BRB) breakdown, a pivotal contributor to multiple retinal vascular diseases, manifests as progressive increase in permeability induced by various pathological stimuli. The functional plasticity of endothelial cells can be intricately shaped metabolic alteration. However, little is known about the mechanisms through which disorders trigger dissolution inter-vascular junctions and selective approaches targeting homeostasis. Herein, we identify AMPK-associated fatty acid oxidation (FAO) inhibition critical driver dysfunction via exacerbating redox imbalance. Pharmacological facilitation FAO ginsenoside Rd (Rd) suppresses BRB collapse other secondary damage diabetic retinopathy (DR). Mechanistically, targets GPR30 phosphorylate AMPK PKA-LKB1-AMPK kinase cascade. activation revitalizes hyperglycemia-compromised FAO, then sustains mitochondrial NADPH regeneration emphasis on IDH2 at levels, including substrate supply, transcription, post-translational modifications. Therefore, alleviates disruption integrity driven oxidative stress, with vasculoprotection diminished knockdown pharmacological attenuation AMPK. These findings collectively reveal previously-unanticipated role heightened leakage, highlight potential translational application agonism mitigate dysfunction, providing regulatory therapeutic strategy for DR.