Targeting DRP1 attenuates ferroptosis and delays the progression of diabetic retinopathy

Diabetic retinopathy (DR), the leading cause of blindness among working-age adults, is driven by largely undefined modes of retinal microvascular cell death. We asked whether the mitochondrial fission GTPase dynamin-related protein 1 (DRP1) governs ferroptotic injury in this setting. In cultured human retinal microvascular endothelial cells (HRMECs) exposed to high glucose (40 mM) or to the ferroptosis agonist RSL3, DRP1 expression rose in parallel with ferroptotic signaling: ACSL4 and PBP1 were up-regulated, SLC7A11 and GPX4 were down-regulated, intracellular ROS and Fe²⁺ accumulated, glutathione plummeted, and mitochondria became swollen with fragmented cristae. Lentiviral DRP1 knock-down reversed each of these alterations. In streptozotocin-diabetic Sprague-Dawley rats, retinal endothelial cells displayed similar ferroptotic activation, whereas daily administration of the DRP1 inhibitor Mdivi-1 restored antioxidant indices and preserved mitochondrial ultrastructure. Collectively, the data identify DRP1-mediated ferroptosis as a critical driver of microvascular injury in DR and position DRP1 inhibition as a plausible therapeutic strategy for the disease.