Dulaglutide promotes mitophagy by regulating copper metabolism and protects retinal pigment epithelial cells from high glucose-induced damage

Background Copper metabolism dysregulation contributes to mitochondrial damage in diabetic retinopathy (DR). This study investigated whether dulaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, alleviates DR by regulating copper homeostasis. Methods Clinical serum analysis, high glucose-exposed ARPE-19 cells, and diabetic rat models were used. Measurements included copper/ceruloplasmin levels, oxidative stress, mitochondrial function, and mitophagy markers. Results Clinical test results show that the levels of ceruloplasmin and copper in the serum of patients with proliferative diabetic retinopathy (PDR) are significantly higher than those of diabetic patients. High glucose induced copper/ceruloplasmin accumulation, downregulated ATP7B/SOD1/COX11/ATP7A/CCS, upregulated SCO1/DMT1, and impaired mitochondrial function in retinal pigment epithelial (RPE) cells. Dulaglutide reversed these effects, reducing oxidative stress and inflammation while restoring mitochondrial integrity. Crucially, it activated PINK1/Parkin-mediated mitophagy. The protective effects were abolished by CuSO 4 , confirming copper homeostasis as central to its mechanism. In diabetic rats, dulaglutide corrected retinal copper metabolism abnormalities, ameliorated histopathological damage, and enhanced mitophagy, thereby preserving mitochondrial function and alleviating diabetic retinopathy. Conclusion Dulaglutide ameliorates DR by correcting copper dysregulation and promoting mitophagy, highlighting copper homeostasis as a potential therapeutic target.