Mitochondrial unfolded protein response in diabetic retinopathy: biomarker identification and mechanistic exploration

Diabetic retinopathy (DR) is a common microvascular complication of diabetes. The mitochondrial unfolded protein response (UPRmt) is a key stress-adaptive mechanism, yet its role in DR remains unclear. This study aimed to investigate the involvement of UPRmt-related genes (MRGs) in DR. Transcriptomic datasets (GSE221521 and GSE189005) were analyzed to identify differentially expressed MRGs. Weighted gene co-expression network analysis (WGCNA), machine learning, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to screen and validate biomarkers. Functional enrichment, nomogram construction, immune infiltration analysis, drug prediction, molecular docking, and regulatory network exploration were performed. GPR52 and FKBP9 were consistently upregulated in DR and showed good diagnostic potential (area under the curve [AUC ≥ 0.7]). A nomogram based on their expression demonstrated high predictive accuracy. Enrichment analysis suggested their roles in PI3K/Akt, Toll-like receptor, and neurotrophin signaling. FKBP9 correlated with altered CD8⁺ T cell and NK cell infiltration. Differential expression of CXCL9 and GZMA supported immune dysregulation. Molecular docking indicated stable interactions with small molecules, including ethinyl estradiol and bisphenol A. POU2F1 and several miRNAs were identified as potential regulators. GPR52 and FKBP9 may serve as UPRmt-related biomarkers in DR, contributing to metabolic and immune dysregulation. These findings offer insights into DR pathogenesis and may inform future personalized diagnostic and therapeutic strategies.