Cross-Compartment Proteomic Signatures in Human Diabetic Retinopathy: A Systematic Review and Meta-Analysis

Diabetic retinopathy (DR) is a leading cause of preventable blindness, with complex molecular pathophysiology spanning multiple biological compartments. This systematic review and meta-analysis aimed to synthesize proteomic findings from human DR studies to identify consistent cross-compartment molecular signatures and evaluate their clinical translation potential.

Following a prespecified PRISMA protocol, we searched databases and registries to September 2025. Two reviewers independently screened, extracted, and assessed risk of bias using validated tools. Proteomic results were standardized to log₂ fold-change (Log2FC) with reconstructed SEs where necessary. Random-effects multilevel models (REML) incorporated protein- and study-level variance. Prespecified subgroup analyses (aqueous, vitreous, plasma), meta-regression (compartment, protein family, interactions), and diagnostics (Egger's test, trim-and-fill, leave-one-out) probed robustness. Qualitative synthesis integrated 28 eligible studies across vitreous, aqueous, plasma/serum, tears, and urine.

Twenty-eight studies contributed data. Quantitative synthesis showed overall protein upregulation in DR (Log2FC = 1.49; 95% CI: 0.72-2.27). Subgroup analyses demonstrated strong and consistent effects in vitreous (Log2FC = 2.41) and aqueous (1.28 humors, with plasma estimates weaker and more heterogeneous. Fibrinogen chains (FGA, FGB, FGG) were robustly upregulated across compartments and exceeded complement proteins (β = +1.41; p < 0.001). Publication-bias adjustment (trim-and-fill, k₀ = 5) yielded a reduced but still significant effect (Log2FC = 1.10). Qualitative evidence highlighted vitronectin, RBP4, prothrombin, and afamin as additional stage-specific candidates, while tear- and urine-based markers showed potential for noninvasive screening.

This first integrated systematic review and meta-analysis of multicompartment proteomic studies in diabetic retinopathy shows consistent upregulation of fibrinogen chains across ocular compartments, highlights vitronectin and stage-specific proteins as additional candidates, and establishes a rigorous evidence base to guide biomarker validation and clinical translation.