{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T17:08:26Z","timestamp":1778605706167,"version":"3.51.4"},"reference-count":80,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Glaucoma remains a primary cause of blindness, yet its pathogenesis often extends beyond intraocular pressure (IOP). This review integrates four converging lines of metabolic evidence\u2014aqueous humor (AH) metabolomics, kynurenine pathway (KP) activity, tetrahydrobiopterin (H4BIP) biology, and NAD\/one-carbon dysfunction\u2014into a testable framework for retinal ganglion cell vulnerability. By utilizing a systematic AH metabolomics atlas covering glaucoma, pseudoexfoliation, and diabetes on a standardized HILIC-LC-HRMS platform, we demonstrate that, while aromatic amino acid elevations are non-specific markers, kynurenine monooxygenase (KMO) upregulation is a condition-specific glaucoma signature. These local findings are corroborated by systemic evidence: POAG patients exhibit significant folic acid deficiency (p = 0.007) and elevated alpha-1-antitrypsin (AAT). Critically, AAT correlates inversely with both serum folate (rs = \u22120.485, p &lt; 0.001) and retinal nerve fiber layer thickness (rs = \u22120.386, p = 0.017), providing the first in-patient evidence linking systemic inflammation to structural optic nerve damage. We conclude that KMO serves as a critical enzymatic node linking tryptophan metabolism, H4BIP availability, and NAD synthesis. These results characterize glaucoma as a disease of progressive cofactor failure and define a research agenda for multimodal metabolic neuroprotection.<\/jats:p>","DOI":"10.3390\/ijms27104311","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T16:04:36Z","timestamp":1778601876000},"page":"4311","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Metabolic Architecture of Glaucoma: A Unified Framework of Cofactor Failure and Kynurenine Dysregulation"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8395-2255","authenticated-orcid":false,"given":"Liva","family":"Caikovska","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Riga Stradins University, LV-1007 Riga, Latvia"},{"name":"Clinic of Ophthalmology, Pauls Stradins Clinical University Hospital, LV-1002 Riga, Latvia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberts","family":"Veitners","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Riga Stradins University, LV-1007 Riga, Latvia"},{"name":"Clinic of Ophthalmology, Pauls Stradins Clinical University Hospital, LV-1002 Riga, Latvia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Lavrinovica","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Riga Stradins University, LV-1007 Riga, Latvia"},{"name":"Clinic of Ophthalmology, Pauls Stradins Clinical University Hospital, LV-1002 Riga, Latvia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8282-8685","authenticated-orcid":false,"given":"Juris","family":"Vanags","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Riga Stradins University, LV-1007 Riga, Latvia"},{"name":"Clinic of Ophthalmology, Pauls Stradins Clinical University Hospital, LV-1002 Riga, Latvia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristaps","family":"Klavins","sequence":"additional","affiliation":[{"name":"Institute of Biomaterials and Bioengineering, Faculty of Natural Sciences and Technology, Riga Technical University, LV-1048 Riga, Latvia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0644-350X","authenticated-orcid":false,"given":"Guna","family":"Laganovska","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Riga Stradins University, LV-1007 Riga, Latvia"},{"name":"Clinic of Ophthalmology, Pauls Stradins Clinical University Hospital, LV-1002 Riga, Latvia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6371-7362","authenticated-orcid":false,"given":"Arturs","family":"Zemitis","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Riga Stradins University, LV-1007 Riga, Latvia"},{"name":"Clinic of Ophthalmology, Pauls Stradins Clinical University Hospital, LV-1002 Riga, Latvia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1016\/j.ophtha.2014.05.013","article-title":"Global Prevalence of Glaucoma and Projections of Glaucoma Burden through 2040: A Systematic Review and Meta-Analysis","volume":"121","author":"Tham","year":"2014","journal-title":"Ophthalmology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1001\/jama.2014.3192","article-title":"The pathophysiology and treatment of glaucoma: A review","volume":"311","author":"Weinreb","year":"2014","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1038\/s41433-018-0042-2","article-title":"Normal tension glaucoma: Review of current understanding and mechanisms of the pathogenesis","volume":"32","author":"Killer","year":"2018","journal-title":"Eye"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.preteyeres.2012.07.001","article-title":"Critical pathogenic events underlying progression of neurodegeneration in glaucoma","volume":"31","author":"Calkins","year":"2012","journal-title":"Prog. 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