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The primary site of damage in Stargardt disease is the retinal pigment epithelium (RPE), which safeguards photoreceptor health and function. Progressive loss of RPE integrity precedes visual deficits, yet insight into mechanisms driving RPE dysfunction and how this influences disease pathogenesis remains elusive. Here, we addressed this in cell-based and pigmented\n                  <jats:italic>\n                    Abca4\n                    <jats:sup>-\/-<\/jats:sup>\n                  <\/jats:italic>\n                  Stargardt mice models using super-resolution imaging, bioinformatics, and biochemical approaches. We show that ceramide accumulation induced by bisretinoid-mediated overactivation of acid sphingomyelinase (ASM) in\n                  <jats:italic>\n                    Abca4\n                    <jats:sup>-\/-<\/jats:sup>\n                  <\/jats:italic>\n                  RPE selectively disrupts Rab GTPases and ESCRT machinery involved in apical membrane trafficking and small extracellular vesicle (EV) biogenesis. Consequently, connexin 43 (Cx43) is misrouted from cell-cell junctions into EVs that are released apically by the RPE. This compromises RPE integrity and promotes subretinal immune cell recruitment, leading to photoreceptor dysfunction. Pharmacological ASM inhibition normalizes EV biogenesis and restores Cx43 localization. Decreasing RPE ceramide safeguards RPE structural integrity, limits subretinal microglia, and improves visual function in\n                  <jats:italic>\n                    Abca4\n                    <jats:sup>-\/-<\/jats:sup>\n                  <\/jats:italic>\n                  mice. This study underscores the importance of the RPE as a communication hub in the retina and identifies ASM as a potential therapeutic target to prevent progressive vision loss.\n                <\/jats:p>","DOI":"10.64898\/2026.02.20.706984","type":"posted-content","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T03:15:14Z","timestamp":1771816514000},"source":"Crossref","is-referenced-by-count":0,"title":["Acid sphingomyelinase inhibition restores RPE homeostasis and photoreceptor function in preclinical Stargardt macular degeneration models"],"prefix":"10.64898","author":[{"given":"Colin J.","family":"Germer","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, School of Medicine, University of California, San Francisco, CA, USA"},{"name":"Pharmaceutical Sciences and Pharmacogenomics Graduate Program, School of Pharmacy, University of California, San Francisco, CA, USA"},{"name":"Jules Stein Eye Institute, University of California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, School of Medicine, University of California, San Francisco, CA, USA"},{"name":"Pharmaceutical Sciences and Pharmacogenomics Graduate Program, School of Pharmacy, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valencia","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, School of Medicine, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Espinosa Lima","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, School of Medicine, University of California, San Francisco, CA, USA"},{"name":"Developmental and Stem Cell Biology Graduate Program, School of Pharmacy, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nilsa R.","family":"La Cunza","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, School of Medicine, University of California, San Francisco, CA, USA"},{"name":"Pharmaceutical Sciences and Pharmacogenomics Graduate Program, School of Pharmacy, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li Xuan","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, School of Medicine, University of California, San Francisco, CA, USA"},{"name":"School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samir Ranjan","family":"Panda","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, School of Medicine, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Iorio","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanny M.","family":"Elahi","sequence":"additional","affiliation":[{"name":"Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aparna","family":"Lakkaraju","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, School of Medicine, University of California, San Francisco, CA, USA"},{"name":"Pharmaceutical Sciences and Pharmacogenomics Graduate Program, School of Pharmacy, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026022416550464000_2026.02.20.706984v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2021.101029"},{"key":"2026022416550464000_2026.02.20.706984v1.2","doi-asserted-by":"crossref","first-page":"101036","DOI":"10.1016\/j.preteyeres.2021.101036","article-title":"Structure and function of ABCA4 and its role in the visual cycle and Stargardt macular degeneration","volume":"89","year":"2022","journal-title":"Prog Retin Eye Res"},{"key":"2026022416550464000_2026.02.20.706984v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2011.12.001"},{"key":"2026022416550464000_2026.02.20.706984v1.4","doi-asserted-by":"crossref","unstructured":"Tan LX , Germer CJ , La Cunza N , and Lakkaraju A . 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