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Ferroptosis is an iron-dependent form of non-apoptotic cell death characterized by the accumulation of lipid peroxides to a lethal level, which plays an important role in retinal diseases. However, it remains unknown whether A2E functions as a physiological trigger for eliciting blue light-induced ferroptosis of RPE cells.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>A2E-loaded RPE cells and <jats:italic>Abca4<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              <jats:italic>Rdh8<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup> mice were exposed to blue light, respectively. Western blotting, immunofluorescence staining, reactive oxygen species (ROS) staining, intracellular iron staining, lipid peroxidation staining, fundus imaging, optical coherence tomography (OCT), hematoxylin\u2013eosin (HE) staining, and electroretinography (ERG) were utilized to elucidate the role of blue light in A2E induced ferroptosis in the RPE and its potential mechanisms.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Exposure of A2E to blue light promoted ferroptotic cell death in RPE cells by elevating ferrous ion (Fe<jats:sup>2+<\/jats:sup>) levels and inhibiting the solute carrier family 7 membrane 11 (SLC7A11)-glutathione\u00a0(GSH)-glutathione peroxidase 4 (GPX4) axis. GPX4 inactivation and ROS generated by Fe<jats:sup>2+<\/jats:sup>\u00a0overload and\u00a0GSH depletion precipitated\u00a0lipid peroxidation\u00a0and subsequent ferroptosis in A2E-containing RPE cells upon exposure to blue light. In addition to GSH supplement, repressing either Fe<jats:sup>2+<\/jats:sup>\u00a0by deferiprone (DFP) or lipid peroxidation with ferrostatin-1 (Fer-1) significantly protected RPE cells against ferroptosis caused by blue light illumination of A2E.\u00a0<jats:italic>Abca4<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              <jats:italic>Rdh8<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\u00a0mice featured by an accelerated deposition of A2E in the RPE is an\u00a0animal model\u00a0for STGD1 and dry AMD. It was observed that ferroptosis was indeed present in the RPE of\u00a0<jats:italic>Abca4<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              <jats:italic>Rdh8<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\u00a0mice following exposure to blue light. Notably, alleviating ferroptosis by intraperitoneally injected Fer-1 effectively rescued retinal function and ameliorated RPE\/photoreceptor degeneration in blue light-exposed\u00a0<jats:italic>Abca4<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              <jats:italic>Rdh8<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\u00a0mice.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Our results suggest the importance of blue light in A2E-mediated ferroptosis in the RPE, and deeply broaden the understanding of mechanisms underlying RPE atrophy arising from lipofuscin accumulation in STGD1 and dry AMD.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s11658-025-00700-2","type":"journal-article","created":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T16:07:57Z","timestamp":1740154077000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Exposure of A2E to blue light promotes ferroptosis in the retinal pigment epithelium"],"prefix":"10.1186","volume":"30","author":[{"given":"Bo","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunhuan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuling","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingjian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingmeng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiying","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5906-5675","authenticated-orcid":false,"given":"Yalin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,21]]},"reference":[{"issue":"5","key":"700_CR1","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1016\/j.exer.2005.01.007","volume":"80","author":"JR Sparrow","year":"2005","unstructured":"Sparrow JR, Boulton M. 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