{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T06:30:49Z","timestamp":1790922649730,"version":"4.1.0"},"reference-count":200,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"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":["82174444"],"award-info":[{"award-number":["82174444"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82174444"],"award-info":[{"award-number":["82174444"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Photoreceptor (PR) degeneration is a shared pathological feature of multiple blinding retinal diseases. This narrative review examines the mechanisms underlying PR vulnerability to ferroptosis-associated lipid-peroxidation injury, with emphasis on three interconnected features: the marked enrichment of docosahexaenoic acid (DHA) and other polyunsaturated fatty acids (PUFAs) in PR outer-segment disc membranes; the chronically high metabolic demand of PRs and the specialized spatial organization of their mitochondria; and retinal pigment epithelium (RPE)\u2013PR metabolic coupling, including outer-segment renewal and phagocytic turnover, glucose transport and lactate shuttling, and visual-cycle\u2013related all-trans-retinal (atRAL) clearance and bisretinoid accumulation. We also summarize antioxidant defense systems centered on the cystine\/glutamate antiporter (xCT)\u2013glutathione (GSH)\u2013glutathione peroxidase 4 (GPX4) axis and mitochondrial GPX4 (mtGPX4), which restricts iron-dependent lipid peroxidation in PRs. We propose that highly oxidizable membrane phospholipid substrates, mitochondrial homeostatic imbalance, and impaired RPE\u2013PR metabolic coupling may collectively shape PR susceptibility to ferroptosis-associated injury. From a therapeutic perspective, this framework supports multitarget strategies designed to interrupt lipid-peroxidation propagation, stabilize mitochondrial redox homeostasis and quality-control mechanisms, and restore RPE\u2013PR metabolic support and local iron-buffering capacity.<\/jats:p>","DOI":"10.3390\/cimb48060616","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T05:46:28Z","timestamp":1781588788000},"page":"616","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Photoreceptor Vulnerability to Ferroptosis: Membrane Phospholipid Peroxidation, Mitochondrial Homeostasis, and RPE\u2013Photoreceptor Coupling"],"prefix":"10.3390","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3713-0373","authenticated-orcid":false,"given":"Yue","family":"Sun","sequence":"first","affiliation":[{"name":"Eye School, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaorui","family":"Xu","sequence":"additional","affiliation":[{"name":"Eye School, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanxia","family":"Wu","sequence":"additional","affiliation":[{"name":"Eye School, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Eye School, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China"},{"name":"Eye Health with Traditional Chinese Medicine Key Laboratory of Sichuan Province, Chengdu 610075, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5324-4736","authenticated-orcid":false,"given":"Xuejing","family":"Lu","sequence":"additional","affiliation":[{"name":"Eye School, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China"},{"name":"Eye Health with Traditional Chinese Medicine Key Laboratory of Sichuan Province, Chengdu 610075, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1016\/S0140-6736(22)02609-5","article-title":"Age-related macular degeneration","volume":"401","author":"Guymer","year":"2023","journal-title":"Lancet"},{"key":"ref_2","unstructured":"GBD 2021 Global AMD Collaborators (2025). 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