Association of miRNA-126 expression with diabetic retinopathy: a systematic review and meta-analysis Background Diabetic retinopathy (DR) is a leading cause of vision impairment in individuals with diabetes. Identifying reliable biomarkers for early diagnosis and disease progression is critical for improving patient outcomes. Emerging evidence suggests that miRNA-126 plays a crucial role in vascular homeostasis and endothelial function, which are key factors in the pathogenesis of diabetic retinopathy (DR). Understanding its expression patterns in DR could provide valuable insights into its potential as a biomarker for early detection and disease progression. Objectives To systematically review and analyze the association between miRNA-126 expression levels and diabetic retinopathy, assessing its presence, severity, and potential as a biomarker through meta-analysis. Methods A comprehensive literature search was conducted in PubMed, Scopus, ScienceDirect, and PubMed Central, following PRISMA checklist. Observational studies comparing miRNA-126 expression levels between diabetic patients with and without DR were included. Data extraction was performed using the Covidence systematic review software, and quality assessment was conducted with the Newcastle-Ottawa Scale. A meta-analysis was conducted to determine pooled effect sizes, with heterogeneity assessed using I² statistics. Meta-regression and sensitivity analyses were performed to explore sources of variability. Results The meta-analysis demonstrated a general trend of reduced miRNA-126 expression in DR patients compared to non-DR individuals. However, substantial heterogeneity was observed across studies (I² = 73.6%–91.6%), likely due to differences in study design, patient characteristics, and miRNA quantification methods. Subgroup analysis revealed a stronger negative mean difference in miRNA-126 expression among type 2 diabetes mellitus (T2DM) patients compared to type 1 diabetes mellitus (T1DM) patients. Sensitivity analysis showed that specific studies with extreme effect sizes influenced the overall findings. Despite these limitations, one analysis yielded a statistically significant association between reduced miRNA-126 levels and DR (MD = -0.33, 95% CI: -0.62 to -0.04, p = 0.0238). Conclusion This study highlights miRNA-126 as a potential biomarker for DR, with a consistent trend toward reduced expression in affected individuals. However, the significant heterogeneity across studies limits the strength of the pooled evidence. Standardized miRNA quantification protocols, larger sample sizes, and uniform study designs are needed to validate its diagnostic utility. Future research should explore miRNA-126 in combination with other biomarkers to enhance the accuracy of DR detection and monitoring. Keywords: Diabetic retinopathy, miRNA-126, biomarkers, endothelial dysfunction, angiogenesis, retinal vascular permeability.