An Integrated Multi-Omics Analysis Identifies Oxeiptosis-Related Biomarkers in Diabetic Retinopathy

Area of Science:

• Genomics and Bioinformatics
• Ophthalmology
• Cell Biology

Background:

• Diabetic retinopathy (DR) is a leading cause of blindness with limited early biomarkers and targeted therapies.
• Oxidative stress is implicated in DR pathogenesis, but the role of oxeiptosis, a specific cell death pathway, is understudied.
• Existing research lacks comprehensive multi-omics approaches to elucidate DR mechanisms.

Purpose of the Study:

• To investigate the role of oxeiptosis-related pathways in diabetic retinopathy (DR) using an integrated multi-omics approach.
• To identify novel candidate biomarkers and therapeutic targets for DR.
• To explore the causal genetic factors and cellular mechanisms underlying DR pathogenesis.

Main Methods:

• Integrated transcriptomic profiling, two-sample Mendelian randomization (MR), and machine learning-based feature selection.
• Single-cell RNA sequencing (scRNA-seq) to analyze gene expression patterns in specific cell types.
• Functional enrichment analysis, immune deconvolution, and diagnostic nomogram construction for validation.

Main Results:

• Elevated oxeiptosis scores were observed in DR blood samples.
• MR analysis identified CASP2 and PLEC as key genes associated with DR risk and protection.
• A diagnostic nomogram incorporating CASP2 and PLEC demonstrated robust DR prediction (AUC = 0.811).
• scRNA-seq revealed distinct expression patterns of CASP2 and PLEC in disease-relevant retinal cells, linked to immune activation.

Conclusions:

• This study establishes an integrated multi-omics framework implicating oxeiptosis in DR.
• CASP2 and PLEC are nominated as putatively causal, biologically relevant candidate biomarkers for DR.
• These genes represent potential therapeutic targets for the treatment of diabetic retinopathy.