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We used our previously established immortalized FECD cells (iFECD) that harbor CTG repeat expansion in\n                    <jats:italic>TCF4<\/jats:italic>\n                    and CRISPR\/Cas9 genome editing to generate an isogenic counterpart (iFECD\n                    <jats:italic>TCF4<\/jats:italic>\n                    \u0394CTG) in which the expansion was deleted. Comprehensive proteomic analysis was then performed using tandem mass tag (TMT)-labeled quantitative LC-MS\/MS. The resulting data were subjected to differential expression analysis, functional enrichment analysis, and protein-protein interaction network construction to elucidate the molecular impact of the CTG repeat expansion. Deletion of the CTG repeat expansion significantly altered the corneal endothelial proteome, with 90 upregulated and 111 downregulated proteins (|log\n                    <jats:sub>2<\/jats:sub>\n                    fold change| \u2265 0.5,\n                    <jats:italic>P<\/jats:italic>\n                    -value\u2009&lt;\u20090.05). Functional enrichment analysis revealed that the downregulated proteins were predominantly associated with extracellular matrix organization and cell\u2013substrate adhesion pathways, while the upregulated proteins were enriched in interferon signaling and antigen-processing pathways. The most significantly upregulated proteins included neuropilin-1, Cip1-interacting zinc finger protein, and protein-glutamine gamma-glutamyltransferase 2, while protein phosphatase 1 regulatory subunit 14\u00a0C, alpha-crystallin B chain, and 14-3-3 protein sigma showed the greatest downregulation. Our findings demonstrate that\n                    <jats:italic>TCF4<\/jats:italic>\n                    CTG repeat expansion significantly impacts the corneal endothelial proteome, particularly affecting the extracellular matrix and cell adhesion proteins that likely contribute to guttae formation. These proteomic alterations provide mechanistic insights connecting trinucleotide repeat expansion to endothelial dysfunction and suggest potential therapeutic targets for FECD.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-43789-x","type":"journal-article","created":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T11:13:52Z","timestamp":1774091632000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TCF4 trinucleotide repeat expansion drives distinct proteomic signatures in Fuchs endothelial corneal dystrophy"],"prefix":"10.1038","volume":"16","author":[{"given":"Taichi","family":"Yuasa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatsuya","family":"Nakagawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetsuro","family":"Honda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Go","family":"Nishiuchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masakazu","family":"Sato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayumi","family":"Tokunaga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makiko","family":"Nakahara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theofilos","family":"Tourtas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ursula","family":"Schl\u00f6tzer-Schrehardt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Friedrich","family":"Kruse","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prema","family":"Padmanabhan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amit","family":"Chatterjee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gajanan","family":"Sathe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivek","family":"Ghose","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Narayanan","family":"Janakiraman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noriko","family":"Koizumi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sailaja V.","family":"Elchuri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoki","family":"Okumura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,3,21]]},"reference":[{"key":"43789_CR1","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/bs.pmbts.2015.04.005","volume":"134","author":"AO Eghrari","year":"2015","unstructured":"Eghrari, A. 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