{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T03:48:15Z","timestamp":1793245695513,"version":"4.5.0"},"reference-count":136,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Oral submucous fibrosis (OSMF) is a chronic, progressive fibrotic disorder with significant malignant potential, and limited effective treatments due to an incomplete understanding of its underlying molecular mechanisms. This narrative review synthesizes current evidence on the key molecular networks involved in OSMF pathogenesis, highlighting the central role of the TGF-\u03b21\/Smad, CTGF, and COL1A1 pathways in maintaining fibroblast activation, supporting myofibroblast activity, and promoting pathological collagen accumulation. It also integrates recent findings on how profibrotic signaling interacts with important angiogenic and epithelial growth factors such as VEGF, FGF, and EGF, creating a stage-dependent fibrotic microenvironment. In early OSMF, increased angiogenic signaling, especially through the VEGF\/PI3K\u2013Akt pathway, helps maintain blood supply. However, as the disease progresses, TGF-\u03b2-induced pathways become dominant, leading to vascular rarefaction, tissue hypoxia, epithelial instability and worsening fibrosis that increases the risk of malignant transformation. By critically appraising molecular, cellular, and translational studies, this review identifies key pathways linking fibrosis, angiogenesis, and epithelial changes in OSMF. It suggests that stage-specific and combined targeting of TGF-\u03b21, CTGF, COL1A1, along with angiogenic and epithelial pathways, may help reverse fibrosis, restore normal tissue perfusion, reduce cancer risk, and support the development of better therapies and biomarkers beyond symptom relief.<\/jats:p>","DOI":"10.3390\/ijms27167204","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T11:02:11Z","timestamp":1786532531000},"page":"7204","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Fibrotic\u2013Angiogenic Signaling Networks in Oral Submucous Fibrosis: Pathobiology and Therapeutic Targeting"],"prefix":"10.3390","volume":"27","author":[{"given":"Samar","family":"Kamran","sequence":"first","affiliation":[{"name":"School of Dental Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0393-9573","authenticated-orcid":false,"given":"Nabeel","family":"Reza","sequence":"additional","affiliation":[{"name":"School of Dental Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zurairah","family":"Berahim","sequence":"additional","affiliation":[{"name":"School of Dental Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saeed Ur","family":"Rahman","sequence":"additional","affiliation":[{"name":"Oral Biology, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar 25000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6147-4192","authenticated-orcid":false,"given":"Johari Yap","family":"Abdullah","sequence":"additional","affiliation":[{"name":"School of Dental Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia"},{"name":"Dental Research Unit, Center for Transdisciplinary Research (CFTR), Saveetha Institute of Medical and Technical Sciences, Saveetha Dental College, Saveetha University, Chennai 602105, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1111\/j.1600-0714.2007.00582.x","article-title":"Nomenclature and classification of potentially malignant disorders of the oral mucosa","volume":"36","author":"Warnakulasuriya","year":"2007","journal-title":"J. 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