Long Non-coding RNA Signatures of Diabetic Retinopathy Across Molecular Dysregulation Diagnostic Discrimination and Neurovascular Pathobiology: A Systematic Review and Meta-analysis

Abstract Diabetic retinopathy (DR) is a vision-threatening microvascular complication of diabetes, and long non-coding RNAs (lncRNAs) regulate retinal vascular injury through angiogenesis, inflammation, endothelial dysfunction, pyroptosis, apoptosis, and stress-response pathways. Original research articles were searched in PubMed, Embase, Cochrane Library, Scopus, Web of Science Core Collection, and Google Scholar from inception to 1 June 2026 without language restrictions. Eligible studies evaluated lncRNA expression, diagnostic performance, susceptibility associations, or DR-related biological mechanisms in human DR populations or relevant experimental models. Two reviewers independently performed screening, data extraction, and risk-of-bias assessment, with third-reviewer adjudication when required. Random-effects meta-analyses synthesized lncRNA expression and diagnostic accuracy. Heterogeneity was assessed using Cochran’s Q and I², reporting bias was examined using funnel plots and Egger regression, and certainty was summarized using GRADE. Twelve studies were included. Seven studies contributed nine expression estimates, showing lncRNA dysregulation in DR compared with controls (pooled correlation = 0.207, 95% CI: 0.152–0.260; P < 0.0001), with low heterogeneity (Q = 8.852; I² = 9.638%). Five studies contributed eight diagnostic estimates. Pooled sensitivity was 75.0% (95% CI: 62.0%–84.6%; P < 0.0001 ; I² = 95.46%), pooled specificity was 79.5% (95% CI: 71.8%–85.5%; P < 0.0001; I² = 90.16%), and mean area under the curve (AUC) was 0.788 (95% CI: 0.719–0.856; P < 0.0001; I² = 81.12%). Mechanistic synthesis implicated vascular endothelial growth factor (VEGF)-mediated angiogenesis, inflammatory signaling, endothelial dysfunction, pericyte pyroptosis, Wnt/nuclear factor kappa B (NF-κB) activity, and retinal cell injury. lncRNAs demonstrate consistent dysregulation, moderate diagnostic discrimination, and biologically coherent involvement in DR pathobiology, supporting their relevance as circulating biomarkers and therapeutic targets for precision-stage DR research.