Effects of Polyunsaturated Fatty Acids, Specifically Omega-3, on Diabetic Retinopathy—A Systematic Integrative Review

Background/Objectives: Diabetic retinopathy (DR) is a leading cause of vision loss worldwide, and its pathology is driven by chronic hyperglycemia, elevated oxidative stress, inflammation, and microvascular dysfunction. Polyunsaturated fatty acids (PUFAs), particularly omega-3 and omega-6 fatty acids, influence inflammatory and angiogenic pathways, but their role in DR prevention and progression remains uncertain. This integrative review synthesizes current evidence on the effects of PUFAs in DR. Methods: A comprehensive literature search was conducted and eligible studies included human cell culture, animal model, observational, Mendelian randomization, and interventional studies. A total of 44 studies meeting inclusion criteria were systematically analyzed and categorized by study design. Results: Human trials with whole-diet/complex supplements suggest that higher intake or circulating levels of omega-3 PUFAs, particularly docosahexaenoic acid (DHA), are associated with reduced risk and severity of DR. A Mediterranean diet enriched with omega-3 sources demonstrated consistent protective associations. However, randomized controlled trials using isolated omega-3 supplementation reported mixed findings, with some showing no significant effect on disease progression (e.g., ASCEND). Mechanistic studies indeed support biological plausibility, demonstrating that omega-3 PUFAs reduce oxidative stress, inhibit inflammatory signaling, and modulate angiogenesis by attenuating vascular endothelial growth factor activity. Emerging evidence also suggests the potential protective role of certain omega-6 fatty acids, though findings remain heterogeneous. Conclusions: PUFAs, particularly omega-3 fatty acids, may play a protective role in DR through anti-inflammatory, antioxidant, and anti-angiogenic mechanisms. These outcomes appear influenced by dietary context, dosage, and disease stage, highlighting the need for additional long-term, well-designed studies.