Ferroptosis in diabetic retinopathy: cellular heterogeneity, progression, and therapeutic targets.

The retina characterized by high energy metabolism and contains the highest polyunsaturated fatty acid (PUFA) content of phospholipids among all organs. Under hyperglycemic conditions, elevated oxidative stress exacerbates lipid peroxidation and promotes ferroptosis, contributing to the progression of diabetic retinopathy (DR). However, the susceptibility of different retinal cell types to ferroptosis and its implications across DR stages remain understudied. This review summarizes the key mechanisms of DR and ferroptosis, and examines the respective susceptibility of retinal pigment epithelium (RPE) cells, photoreceptor cells (PRs), Müller cells and endothelial cells (ECs) to ferroptosis under hyperglycemic stress. Moreover, the cell type-specific ferroptosis exerts distinct pathological effects at different stages of DR progression, including neurodegeneration, inflammation, blood-retinal barrier (BRB) destruction and neovascularization. Finally, we highlight emerging research directions, focusing particularly on metabolic memory and intercellular crosstalk mechanisms underlying ferroptosis. By elucidating these pathways, this review aims to identify precise therapeutic targets to delay DR progression.