Peroxisome Proliferator-activated Receptors in Diabetic Retinopathy: Pathophysiologic Insights and Emerging...

Diabetic retinopathy (DR) is a leading cause of vision loss among working-age adults and one of the most frequent complications of diabetes mellitus. Current therapies, including laser photocoagulation and intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents, are effective only in advanced disease and remain invasive and palliative. The multifactorial pathogenesis of DR involves hyperglycemia-driven oxidative stress, chronic inflammation, dyslipidemia, and disruption of the blood-retinal barrier. Peroxisome proliferator-activated receptors (PPARs) have emerged as key regulators of metabolic and inflammatory signalling in the retina. PPAR-alpha agonists, such as fenofibrate and pemafibrate, exert antioxidant, anti-inflammatory, and vasoprotective effects, whereas PPAR-gamma agonists (e.g. pioglitazone) improve insulin sensitivity and attenuate oxidative damage, albeit with safety concerns such as fluid retention. Dual PPARα/γ agonists, including saroglitazar, provide synergistic benefits by reducing leukostasis, neovascularization, and inflammatory signalling, whereas PPAR-β/δ is gaining attention for its role in retinal energy metabolism. In parallel, non-PPAR targets, such as the advanced glycation end product-receptor for advanced glycation end product (AGE-RAGE) axis, VEGF signalling, aldose reductase, and adenosine monophosphate-activated protein kinase pathways, represent complementary mechanisms. Natural compounds (e.g. curcumin, resveratrol), statins, and metabolic modulators have demonstrated promising preclinical efficacy. Targeting both PPAR and non-PPAR pathways may enable preventive and multimodal management of DR. Future efforts should prioritize early-stage interventions, combination strategies, and innovative ocular drug-delivery systems to overcome current therapeutic limitations and shift from reactive to preventive care.