{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T05:26:02Z","timestamp":1764480362607,"version":"3.46.0"},"reference-count":88,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Inherited retinal degenerations (IRDs), driven by pathogenic mutations, often involve primary dysfunction of the retinal pigment epithelium (RPE)\u2014a pathogenic feature shared with atrophic age-related macular degeneration (aAMD), despite aAMD\u2019s multifactorial etiology. Prominin-1 (Prom1), traditionally linked to photoreceptor pathology, has an unclear role in RPE homeostasis. We assessed Prom1 expression in C57BL\/6J mouse retina sections and RPE flat mounts using immunohistochemistry and generated Prom1-knockout (KO) mouse RPE cells via CRISPR\/Cas9. Bulk RNA sequencing with DESeq2 and gene set enrichment analysis (GSEA) revealed Prom1-regulated pathways. Prom1-KO cells exhibited upregulation of Grem1, Slc7a11, Serpine2, Il1r1, and IL33 and downregulation of Ablim1, Cldn2, IGFBP-2, BMP3, and OGN. Hallmark pathway interrogation identified reduced expression of PINK1 (mitophagy) and MerTK (phagocytosis), implicating defects in mitochondrial quality control and outer segment clearance. Enrichment analysis revealed activation of E2F\/MYC targets, mTORC1 signaling, oxidative phosphorylation, and TNF\u03b1\/NF-\u03baB signaling, alongside suppression of apical junctions, bile acid metabolism, and Epithelial-Mesenchymal Transition (EMT) pathways. These findings suggest Prom1 safeguards RPE integrity by modulating stress responses, mitochondrial turnover, phagocytosis, metabolism, and junctional stability. Our study uncovers Prom1-dependent signaling networks, providing mechanistic insights into RPE degeneration relevant to both IRD and aAMD, and highlights potential therapeutic targets for preserving retinal health.<\/jats:p>","DOI":"10.3390\/ijms262311539","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T11:19:51Z","timestamp":1764328791000},"page":"11539","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Prominin-1 Regulates Retinal Pigment Epithelium Homeostasis: Transcriptomic Insights into Degenerative Mechanisms"],"prefix":"10.3390","volume":"26","author":[{"given":"Weihong","family":"Huo","sequence":"first","affiliation":[{"name":"Departments of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinggang","family":"Yin","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Purnima","family":"Ghose","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jenny C.","family":"Schafer","sequence":"additional","affiliation":[{"name":"Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3542-8376","authenticated-orcid":false,"given":"Edward","family":"Chaum","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4443-9691","authenticated-orcid":false,"given":"Sujoy","family":"Bhattacharya","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Corradetti, G., Verma, A., Tojjar, J., Almidani, L., Oncel, D., Emamverdi, M., Bradley, A., Lindenberg, S., Nittala, M.G., and Sadda, S.R. 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