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Frontline treatment consists of an anti-inflammatory agent, pentoxifylline, in combination with an antioxidant, Vitamin E, (PENTOX) along with palliative care agents such as corticosteroids, non-steroidal anti-inflammatory agents, muscle relaxants (i.e., botulinum toxin A), or physical therapy for alleviation of symptoms such as pain, inflammation, and lymphedema. However, while efficacious in stabilization and palliation of disease, PENTOX is one of the only established agents with confirmed anti-fibrotic effects in HNSCC. Alternative therapies such as hyperbaric oxygen therapy or superoxide dismutase show efficacy in alleviating acute radiation toxicities but lack a substantial reduction in fibrotic burden. Furthermore, experimental investigations into natural antioxidants, anti-fibrotic agents approved for idiopathic pulmonary fibrosis, mesenchymal stem cell therapy, and general nutritional support, indicate anti-RIF potential, but studies in HNSCC specifically are lacking. This review aims to characterize the pathogenesis of RIF development in the HNSCC disease setting and summarize promising anti-fibrotic agents under investigation for radiation-induced toxicities.<\/jats:p>","DOI":"10.3390\/cells14241969","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T11:17:27Z","timestamp":1765451847000},"page":"1969","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Radiation-Induced Fibrosis (RIF) in Head and Neck Squamous Cell Carcinoma (HNSCC): A Review"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-7448-0775","authenticated-orcid":false,"given":"Molly E.","family":"Muehlebach","sequence":"first","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5601-322X","authenticated-orcid":false,"given":"Sidharth","family":"Pradeep","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Dietetics and Nutrition, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4076-5772","authenticated-orcid":false,"given":"Levi","family":"Arnold","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5208-4336","authenticated-orcid":false,"given":"Anna E.","family":"Arthur","sequence":"additional","affiliation":[{"name":"Department of Dietetics and Nutrition, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory N.","family":"Gan","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sufi Mary","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Barsouk, A., Aluru, J.S., Rawla, P., Saginala, K., and Barsouk, A. 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