Systemic strategies to prevent early diabetic retinopathy: targeting polyunsaturated fatty acid metabolism and eicosanoid signaling

Diabetic retinopathy (DR) is a leading cause of preventable vision loss, yet current therapies primarily address late, VEGF-driven vascular complications rather than early upstream drivers. Emerging evidence indicates that early DR originates from metabolic stress within the retinal neurovascular unit, where dysregulated lipid metabolism, oxidative stress, and inflammation precede visible microvascular damage. Disturbances in polyunsaturated fatty acid (PUFA) metabolism, together with related metabolic stressors such as elevated homocysteine (Hcy), drive lipid dysregulation, oxidative stress, and inflammation preceding visible microvascular damage, promoting endothelial dysfunction and blood-retinal barrier (BRB) breakdown. Hyperglycemia shifts retinal lipid composition toward oxidation-prone omega-6 PUFAs and activates lipoxygenase (LOX), cyclooxygenase (COX), and cytochrome P450 (CYP450) eicosanoid pathways. LOX-derived metabolites such as 12- and 15-HETE stimulate NADPH oxidase, disrupt tight junctions, and promote inflammatory signaling in endothelial and Müller cells. COX-2-driven prostaglandin E2 signaling increases vascular permeability, while CYP450 metabolites and their soluble epoxide hydrolase (sEH) derived products exert context-dependent effects on vascular integrity. Elevated Hcy further enhances oxidative stress and NF-κB activation, amplifying PUFA-mediated inflammatory signaling. These mechanisms identify modifiable upstream targets that complement glycemic control. Higher dietary omega-3 intake and lower omega-6:omega-3 ratios are associated with reduced DR risk, particularly in well-controlled diabetes. Omega-3-rich diets, exercise, and correction of folate and B-vitamin deficiencies may help improve systemic inflammation and retinal barrier integrity. Integrating lipid pathway modulation, nutritional support, and metabolic control with careful ocular monitoring may help slow the progression of DR before irreversible blindness occurs.