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Disruption of this homeostasis causes fibrotic scarring, a leading cause of blindness. Transforming growth factor-\u03b2\/Smad3 signaling drives corneal fibrogenesis, but the distinct roles of Smad2 versus Smad3 remain unclear. Smad2 ablation in neural crest cells using Wnt1-Cre mice triggers spontaneous severe corneal opacification along with massive stromal hypercellularity and fibrosis. The fibrotic phenotype occurs in the absence of injury, indicating that Smad2 is essential for balancing Smad3 activity in driving fibrotic signaling. Single-cell RNA sequencing and virtual knockout of Smad2 reveal prominent activation of Smad3-Yes-associated protein (YAP)\/TEAD2-transcriptional program in Smad2-null corneas. Biochemical assays confirm that Smad2 loss results in increased Smad3 phosphorylation and formation of nuclear Smad3\u2013YAP\u2013TEAD2 complex. This trimeric complex induces the expression of collagen I, connective tissue growth factor, and cyclin D1. Importantly, pharmacologic inhibition of YAP\/TEAD interaction with verteporfin blocks stromal hyperplasia and corneal fibrosis by suppressing the expression of fibrotic and cell cycle genes, which lead to restoration of corneal transparency in Smad2-neural crest-deficient mice. Our findings reveal a unique convergence of YAP\/TEAD and TGF-\u03b2\/Smad3 signaling that can be targeted with verteporfin to prevent corneal scarring and blindness.<\/jats:p>","DOI":"10.3390\/cells15131202","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T10:04:44Z","timestamp":1782986684000},"page":"1202","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Smad2 Preserves Corneal Stromal Homeostasis by Restraining Profibrotic Smad3\/YAP\/TEAD2 Transcriptional Program"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-0602-7131","authenticated-orcid":false,"given":"Ruimei","family":"Zhou","sequence":"first","affiliation":[{"name":"Departments of Surgery, University of Missouri School of Medicine, Columbia, MO 65212, USA"},{"name":"Departments of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO 65212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0489-6567","authenticated-orcid":false,"given":"Dunpeng","family":"Cai","sequence":"additional","affiliation":[{"name":"Departments of Surgery, University of Missouri School of Medicine, Columbia, MO 65212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0297-8649","authenticated-orcid":false,"given":"Shi-You","family":"Chen","sequence":"additional","affiliation":[{"name":"Departments of Surgery, University of Missouri School of Medicine, Columbia, MO 65212, USA"},{"name":"Departments of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO 65212, USA"},{"name":"The Research Service, Harry S. 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