Candidate Glaucoma Biomarkers: From Proteins to Metabolites, and the Pitfalls to Clinical Applications

Simple Summary Glaucoma is a devastating eye disease causing progressive vision loss and consequent irreversible blindness. The global prevalence of glaucoma is estimated at 80 million people, with a projected increase in the number of people affected to 112 million by 2040. The clinical diagnosis of glaucoma usually occurs late, by which time up to 40% of neurosensory cells may be lost. There is an overriding need for early diagnosis systems based on the analysis of glaucoma biomarkers. However, plenty of candidate biomarkers have been published to date in humans, without clear clinical translation. In this review, we have summarized the efforts carried out for the discovery of proteomics- and metabolomics-based glaucoma biomarkers in blood, aqueous humor, tears, and ocular tissues from human subjects. The huge amount of data without real clinical application merits a new integrative approach, allowing future diagnostic tests to be based on local and/or systemic biomarkers of glaucoma. Glaucoma is an insidious group of eye diseases causing degeneration of the optic nerve, progressive loss of vision, and irreversible blindness. The number of people affected by glaucoma is estimated at 80 million in 2021, with 3.5% prevalence in people aged 40-80. The main biomarker and risk factor for the onset and progression of glaucoma is the elevation of intraocular pressure. However, when glaucoma is diagnosed, the level of retinal ganglion cell death usually amounts to 30-40%; hence, the urgent need for its early diagnosis. Molecular biomarkers of glaucoma, from proteins to metabolites, may be helpful as indicators of pathogenic processes observed during the disease's onset. The discovery of human glaucoma biomarkers is hampered by major limitations, including whether medications are influencing the expression of molecules in bodily fluids, or whether tests to validate glaucoma biomarker candidates should include human subjects with different types and stages of the disease, as well as patients with other ocular and neurodegenerative diseases. Moreover, the proper selection of the biofluid or tissue, as well as the analytical platform, should be mandatory. In this review, we have summarized current knowledge concerning proteomics- and metabolomics-based glaucoma biomarkers, with specificity to human eye tissue and fluid, as well the analytical approach and the main results obtained. The complex data published to date, which include at least 458 different molecules al