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This review explores the crucial roles of cysteine and selenocysteine in redox homeostasis and retinal protection. Cysteine, primarily synthesized via the transsulfuration pathway, is the rate-limiting precursor for glutathione (GSH), the most abundant intracellular antioxidant. Selenocysteine enables the enzymatic activity of selenoproteins, particularly glutathione peroxidases (GPXs), which counteract reactive oxygen species (ROS). Experimental evidence from retinal models confirms that depletion of cysteine or selenocysteine results in impaired antioxidant defense and photoreceptor death. Furthermore, dysregulation of these amino acids contributes to the pathogenesis of age-related macular degeneration (AMD), retinitis pigmentosa (RP), and diabetic retinopathy (DR). Therapeutic approaches including N-acetylcysteine, selenium compounds, and gene therapy targeting thioredoxin systems have demonstrated protective effects in preclinical studies. Targeting cysteine and selenocysteine-dependent systems, as well as modulating the KEAP1\u2013NRF2 pathway, may offer promising strategies for managing retinal neurodegeneration. Advancing our understanding of redox mechanisms and their role in retinal cell viability could unlock new precision treatment strategies for retinal diseases.<\/jats:p>","DOI":"10.3390\/biom15081203","type":"journal-article","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T14:46:04Z","timestamp":1755787564000},"page":"1203","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Retinal Gatekeepers: Molecular Mechanism and Therapeutic Role of Cysteine and Selenocysteine"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9929-6376","authenticated-orcid":false,"given":"Eleonora","family":"Maceroni","sequence":"first","affiliation":[{"name":"Department of Life, Health and Environmental Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2737-7970","authenticated-orcid":false,"given":"Annamaria","family":"Cimini","sequence":"additional","affiliation":[{"name":"Department of Life, Health and Environmental Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Quintiliani","sequence":"additional","affiliation":[{"name":"Department of Life, Health and Environmental Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3693-840X","authenticated-orcid":false,"given":"Michele","family":"d\u2019Angelo","sequence":"additional","affiliation":[{"name":"Department of Life, Health and Environmental Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7005-3218","authenticated-orcid":false,"given":"Vanessa","family":"Castelli","sequence":"additional","affiliation":[{"name":"Department of Life, Health and Environmental Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1093\/aob\/mcg023","article-title":"Molecular Biology of the Cell. 4th Edn","volume":"91","author":"Chaffey","year":"2003","journal-title":"Ann. 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