{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:08:41Z","timestamp":1789564121586,"version":"build-2803163510"},"reference-count":112,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82274341"],"award-info":[{"award-number":["82274341"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82274341"],"award-info":[{"award-number":["82274341"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"crossref","award":["2024JJ5304"],"award-info":[{"award-number":["2024JJ5304"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"crossref","award":["2025JJ60633"],"award-info":[{"award-number":["2025JJ60633"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Key Research and Development Program of Hunan Province","award":["2024JK2122"],"award-info":[{"award-number":["2024JK2122"]}]},{"name":"Scientific research project of Hunan Provincial Department of Education","award":["23A0278"],"award-info":[{"award-number":["23A0278"]}]},{"name":"Scientific research project of Hunan Provincial Department of Education","award":["23B0346"],"award-info":[{"award-number":["23B0346"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in older adults and is characterized by progressive dysfunction of the retinal pigment epithelium (RPE). Although genetic susceptibility and environmental exposure both contribute to disease risk, the mechanisms through which chronic metabolic and oxidative stress are integrated into sustained RPE dysfunction remain incompletely understood. Increasing evidence from human AMD donor tissue and experimental RPE models indicates that epigenetic regulation operates at the interface between mitochondrial dysfunction, redox imbalance, and transcriptional remodeling. This review synthesizes current findings on DNA methylation, chromatin accessibility, histone modification, and RNA-based regulation in AMD, with emphasis on their metabolic and mitochondrial context. Studies in human AMD-RPE demonstrate that epigenetic alterations are generally selective rather than global and frequently involve pathways related to mitochondrial maintenance, lipid metabolism, oxidative stress responses, and cellular homeostasis. Mechanistically, mitochondrial dysfunction and reactive oxygen species (ROS) may influence epigenetic regulation through altered Nicotinamide adenine dinucleotide (NAD+) availability, acetyl-CoA metabolism, redox-sensitive chromatin regulation, and modulation of DNA methyltransferase and histone deacetylase activity. Redox-sensitive pathways, including antioxidant signaling, further connect mitochondrial stress to adaptive or maladaptive transcriptional responses in the RPE. Importantly, while several interactions discussed are supported by findings in human AMD tissue, other components of the proposed epigenetic\u2013mitochondrial\u2013redox framework remain inferential or model-based and require further validation. Rather than acting as isolated disease triggers, epigenetic changes are more likely to function as stress-responsive regulatory layers that stabilize transcriptional states over time in a long-lived post-mitotic tissue. We further discuss unresolved questions regarding causality, reversibility, therapeutic feasibility, and stage-specific intervention strategies. Collectively, this framework positions the epigenetic\u2013mitochondrial\u2013redox axis as a unifying model for understanding RPE vulnerability and AMD progression.<\/jats:p>","DOI":"10.3390\/antiox15060713","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T07:36:28Z","timestamp":1780558588000},"page":"713","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Epigenetic\u2013Mitochondrial\u2013Metabolic Crosstalk in Retinal Pigment Epithelium (RPE) Dysfunction in Age-Related Macular Degeneration (AMD)"],"prefix":"10.3390","volume":"15","author":[{"given":"Yijing","family":"Yang","sequence":"first","affiliation":[{"name":"School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China"},{"name":"School of Clinical and Experimental Sciences (CES), Faculty of Medicine, University of Southampton, MP 806, Tremona Road, Southampton SO16 6YD, UK"},{"name":"Institute of Ophthalmology and Otolaryngology of Chinese Medicine, Changsha 410208, China"},{"name":"Changsha Centre for Innovation in Traditional Chinese Medicine Techniques for the Prevention and Treatment of Retinal Diseases and Visual Function Protection, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Deng","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China"},{"name":"Institute of Ophthalmology and Otolaryngology of Chinese Medicine, Changsha 410208, China"},{"name":"Changsha Centre for Innovation in Traditional Chinese Medicine Techniques for the Prevention and Treatment of Retinal Diseases and Visual Function Protection, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Li","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China"},{"name":"Institute of Ophthalmology and Otolaryngology of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pai","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China"},{"name":"Institute of Ophthalmology and Otolaryngology of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9378-1330","authenticated-orcid":false,"given":"Qinghua","family":"Peng","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China"},{"name":"Institute of Ophthalmology and Otolaryngology of Chinese Medicine, Changsha 410208, China"},{"name":"Changsha Centre for Innovation in Traditional Chinese Medicine Techniques for the Prevention and Treatment of Retinal Diseases and Visual Function Protection, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1027-6938","authenticated-orcid":false,"given":"J. Arjuna","family":"Ratnayaka","sequence":"additional","affiliation":[{"name":"School of Clinical and Experimental Sciences (CES), Faculty of Medicine, University of Southampton, MP 806, Tremona Road, Southampton SO16 6YD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e330","DOI":"10.1111\/aos.14589","article-title":"Variations and trends in global disease burden of age-related macular degeneration: 1990\u20132017","volume":"99","author":"Zou","year":"2021","journal-title":"Acta Ophthalmol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e106","DOI":"10.1016\/S2214-109X(13)70145-1","article-title":"Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: A systematic review and meta-analysis","volume":"2","author":"Wong","year":"2014","journal-title":"Lancet Glob. 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