{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T13:02:21Z","timestamp":1790859741918,"version":"4.1.0"},"reference-count":94,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University Scientific Research Grant","award":["RSA 2024"],"award-info":[{"award-number":["RSA 2024"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Glaucoma is increasingly recognized as a multifactorial neurodegenerative optic neuropathy in which intraocular pressure (IOP) is one of several stress amplifiers rather than a sufficient etiological explanation. Vascular dysregulation, mitochondrial and metabolic vulnerability, oxidative stress, excitotoxicity, glial dysregulation, and persistent neuroimmune activation can converge on retinal ganglion cell (RGC) and optic nerve injury. This broader framework is particularly relevant to normal-tension glaucoma (NTG), which represents a large proportion of primary open-angle glaucoma in Asian populations, and to patients who continue to progress despite IOP being maintained within the target range. Consequently, mitochondrial dysfunction, metabolic impairment, oxidative stress, and the associated neuroinflammatory response are not merely downstream adjunctive targets: they are core disease mechanisms and potential treatment targets in pressure-independent and pressure-resistant glaucoma. Coenzyme Q10 (CoQ10), nicotinamide, pyruvate, and citicoline are emerging metabolic and neuroprotective agents whose primary actions involve mitochondrial bioenergetics, redox homeostasis, membrane integrity, and cellular stress responses, with potential secondary effects on neuroinflammatory pathways. Chronic activation of microglia and astrocytes promotes the release of pro-inflammatory cytokines, reactive oxygen species, and apoptotic mediators, leading to RGC degeneration. CoQ10 may counteract these mechanisms through antioxidant activity and stabilization of mitochondrial function; nicotinamide, a precursor of NAD+, may enhance mitochondrial resilience and suppress inflammatory cascades associated with energy failure; pyruvate supports aerobic metabolism and may limit oxidative, inflammatory, and excitotoxic injury; and citicoline supports membrane homeostasis, phospholipid synthesis, neuronal repair, and visual-pathway function. Combined targeting of these interconnected pathways may enhance RGC resilience independently of, and in addition to, IOP reduction. However, current clinical evidence remains insufficient to establish sustained neuroprotection or disease-modifying efficacy. This review examines the interplay among these mechanisms in glaucomatous neurodegeneration and critically discusses the experimental and clinical evidence supporting metabolic and immunometabolic neuroprotective strategies as potential adjuncts to conventional intraocular pressure-lowering therapy.<\/jats:p>","DOI":"10.3390\/molecules31193367","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:50:58Z","timestamp":1790859058000},"page":"3367","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic and Immunometabolic Neuroprotection in Glaucoma: Mitochondrial Dysfunction, Neuroinflammation, and Emerging Therapeutic Strategies"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3725-8211","authenticated-orcid":false,"given":"Alessio","family":"Martucci","sequence":"first","affiliation":[{"name":"Ophthalmology Unit, Department of Experimental Medicine, University of Rome \u201cTor Vergata\u201d, Via Montpellier 1, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Anselmi","sequence":"additional","affiliation":[{"name":"Ophthalmology Unit, Department of Experimental Medicine, University of Rome \u201cTor Vergata\u201d, Via Montpellier 1, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9514-6472","authenticated-orcid":false,"given":"Enrico","family":"Romano","sequence":"additional","affiliation":[{"name":"Department of Sense Organs, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Bello","sequence":"additional","affiliation":[{"name":"Ophthalmology Unit, Department of Experimental Medicine, University of Rome \u201cTor Vergata\u201d, Via Montpellier 1, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Aiello","sequence":"additional","affiliation":[{"name":"Ophthalmology Unit, Department of Experimental Medicine, University of Rome \u201cTor Vergata\u201d, Via Montpellier 1, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaele","family":"Mancino","sequence":"additional","affiliation":[{"name":"Ophthalmology Unit, Department of Experimental Medicine, University of Rome \u201cTor Vergata\u201d, Via Montpellier 1, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8758-6523","authenticated-orcid":false,"given":"Rossella","family":"Russo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Health and Nutritional Sciences, Section of Preclinical and Translational Pharmacology, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Nucci","sequence":"additional","affiliation":[{"name":"Ophthalmology Unit, Department of Experimental Medicine, University of Rome \u201cTor Vergata\u201d, Via Montpellier 1, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.ajo.2025.12.013","article-title":"Global Glaucoma Prevalence: Burden and Projection to 2060","volume":"283","author":"Wang","year":"2026","journal-title":"Am. 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