6-Gingerol reshapes exosomal miR-148b-3p/ACSL4 axis to combat high glucose-induced retinal endothelial ferroptosis

Background Diabetic retinopathy (DR), a leading cause of blindness, is driven by redox imbalance and ferroptosis in retinal endothelial cells. While 6-Gingerol exhibits antioxidant properties, its role in modulating exosome-mediated redox signaling in DR remains unexplored.This study investigates whether 6-Gingerol protects against DR by regulating ferroptosis via the exosomal miR-148b-3p/ACSL4 axis. Methods Human retinal microvascular endothelial cells (HRMECs) were exposed to high glucose (HG) ± 6-Gingerol. Ferroptosis was assessed via lipid ROS, intracellular iron, and key markers (GPX4, ACSL4, FTH1). Exosomal miRNAs were profiled by sequencing, with miR-148b-3p validated as a regulator of ACSL4 through luciferase assays. Functional rescue experiments confirmed pathway specificity. Results 6-Gingerol suppressed HG-induced ferroptosis, reducing lipid ROS by 2.1-fold ( P  < 0.01) and iron accumulation by 1.8-fold ( P  < 0.05), while upregulating GPX4 (3.2-fold, P  < 0.001). Exosomal miR-148b-3p was downregulated under HG but restored by 6-Gingerol (4.5-fold, P  < 0.001). miR-148b-3p directly targeted ACSL4, whose knockdown mimicked 6-Gingerol’s effects, whereas ACSL4 overexpression or miR-148b-3p inhibition abolished protection. Conclusions 6-Gingerol mitigates DR progression by inhibiting ferroptosis through exosomal miR-148b-3p/ACSL4-dependent redox regulation. These findings unveil a novel crosstalk between exosomal miRNAs and iron metabolism, positioning 6-Gingerol as a potential redox-targeted therapy for DR.