Comprehensive Serum Proteomics Uncovers Epigenetic and Inflammatory Pathways Underlying Primary Open-Angle Glaucoma

Glaucoma is a leading cause of irreversible blindness, driven by progressive Retinal ganglion cell loss and optic nerve degeneration. The molecular mechanisms underlying primary open angle glaucoma (POAG) remain unclear, and current intraocular pressure-lowering therapies often do not halt disease progression. Moreover, limited molecular data from Asian patient cohorts restrict population-specific therapeutic development. This study describes comprehensive serum proteomic analysis of age-matched, clinically validated Indian POAG patients to identify molecular markers and pathways linked to glaucomatous neurodegeneration. Optical coherence tomography confirmed significant reductions in the retinal nerve fiber layer, ganglion cell layer thickness, optic nerve head cupping, and neuroretinal rim area in POAG patients. Label-free nano-LC-MS/MS profiling revealed distinct protein expression changes by identifying 22 unique proteins associated with POAG. Dysregulated pathways involve neurodegeneration, inflammation, chromatin remodeling, histone deacetylation, DNA methylation dysregulation, and defective pyroptosis. Decreased structural, neuronal, and immune-inflammatory proteins such as desmoglein-1, contactin-1, CD109, apolipoproteins, optineurin, lumican, cadherin-1, and β2-microglobulin were prominent. Lumican and optineurin showed strong associations with POAG, supporting their biomarker potential. Machine-learning network analysis linked H2BE1, APP, CD163, HSPD1, and B2M to disease progression. Overall, the findings indicate POAG as a metabolically and epigenetically driven neurodegenerative disorder, emphasizing biomarker-based approaches for early diagnosis and RGC-protective therapies.