Beyond glycemia: The influence of systemic inflammation, lipids, and the gut-retina axis in diabetic retinopathy

Table 1 Pathogenic drivers and therapeutic perspectives in diabetic retinopathy

Intervention/target	Reported effects on DR	Retinal mechanism	Evidence level	Representative studies
miRNAs	Dual suppression of VEGF-A and lipid-modulating effects	Suppresses pathological angiogenesis and ceramide accumulation	Preclinical/translational	Experimental studies on miRNA–lipid interaction[94]
Statins	Lower systemic cholesterol; pleiotropic anti-inflammatory effects	Suppresses DR incidence in patients’ population	Low-moderate (observational; limited RCT data)	Population-based cohorts; mechanistic discussion[97]
ASM inhibitors (ceramide axis)	Pro-apoptotic, pro-oxidant ceramide accumulation impairs retinal function and BRB integrity	Suppresses vascular leakage and neuronal loss	Preclinical	ASM inhibition and ceramide modulation studies[70-72]
sEH inhibitors	Preserve anti-inflammatory epoxy fatty acids; normalize oxylipin signaling	Suppresses retinal inflammation and neovascularization	Preclinical	Diabetes-induced retinopathy models[68]
LXR agonists	Enhances ABCA1/ABCG1-mediated cholesterol efflux; suppresses NF-κB-driven inflammation	Suppresses inflammatory cytokines	Preclinical	Experimental retinal models[69]
n-3 PUFA (DHA/EPA, Mediterranean diet)	Precursors of resolvins, protectins, and maresins; anti-inflammatory and oxidative stress reduction; suppresses risk of proliferative DR	Suppresses vascular leakage, oxidative stress, and inflammation; complete DR progression risk reduction in observational cohorts	Moderate-high (preclinical + dietary intervention trials in T2D)	PREDIMED cohort; dietary intervention trials in T2D[64,106]
Fenofibrate (PPARα agonist)	Restores downregulated PPARα; cell-protective effects on endothelial cells; suppresses inflammatory and oxidative stress via cholesterol efflux	Suppresses need for laser therapy; slower DR progression	High (large RCTs + preclinical validation)	FIELD, ACCORD studies[57,58]

DR: Diabetic retinopathy; miRNA: MicroRNA; ASM: Acid sphingomyelinase; sEH: Soluble epoxide hydrolase; LXR: Liver X receptors; PUFA: Polyunsaturated fatty acids; DHA: Docosahexaenoic acid; EPA: Eicosapentaenoic acid; PPARα: Peroxisome proliferator-activated receptor alpha; VEGF-A: Vascular endothelial growth factor-A; BRB: Blood-retinal barrier; ABCA1/ABCG1: ATP-binding cassette transporter A1/G1; NF-κB: Nuclear factor kappa B; RCT: Randomized controlled trial; T2D: Type 2 diabetes.