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We aimed to identify and validate novel genes associated with the regulation of epithelial-to-mesenchymal transition (EMT) in OSF. Genes regulating EMT were identified through differential gene expression analysis, using a LogFC threshold of -1 and +\u20091 and a padj value\u2009&lt;\u20090.05, based on data from GEO datasets and the TCGA-HNSC datasets. The curated EMT genes were correlated with functional cancer states and subjected to clustering to identify candidate genes. Integration of bioinformatics and proteomics led to the discovery of the EMT genes <jats:italic>MMP9<\/jats:italic>, <jats:italic>SPARC<\/jats:italic>, and <jats:italic>ITGA5<\/jats:italic> as novel candidates. Comprehensive pathway and immunohistochemical analyses confirmed their roles in regulating EMT in OSF, oral squamous cell carcinoma (OSCC), and OSF-associated squamous cell carcinoma (OSFSCC). The significant roles of <jats:italic>MMP9<\/jats:italic>, <jats:italic>SPARC<\/jats:italic>, and <jats:italic>ITGA5<\/jats:italic> in fibrosis and malignancy suggest a novel mechanism in which fibrosis-associated type 2 EMT undergoes transition to type 3 EMT, driving OSF towards malignancy.<\/jats:p>","DOI":"10.1038\/s41598-025-87790-2","type":"journal-article","created":{"date-parts":[[2025,1,26]],"date-time":"2025-01-26T12:14:50Z","timestamp":1737893690000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Novel transcripts of EMT driving the malignant transformation of oral submucous fibrosis"],"prefix":"10.1038","volume":"15","author":[{"given":"Smitha Sammith","family":"Shetty","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanaka Sai","family":"Ram Padam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohit","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adarsh","family":"Kudva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pratik","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raghu","family":"Radhakrishnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,26]]},"reference":[{"key":"87790_CR1","unstructured":"GLOBOCAN. 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