Metabolic support protects mucosa from ferroptosis in radiation-induced mucositis

  • Nat Commun. 2025 Dec 8. doi: 10.1038/s41467-025-67214-5.
Weiwei Yu  #  1 ,  Kai Jiao  #  2 ,  Kaiyan Wang  #  1 ,  Xiang Li  #  1 ,  Qianqian Wan  1 ,  Wen Qin  1 ,  Xinyi Hao  1 ,  Meichen Wan  1 ,  Yuxuan Ma  1 ,  Jiao Wu  3 ,  Qing Liu  1 ,  Mei Shi  4 ,  Conrado Aparicio  5  6 ,  Franklin Tay  7 ,  Lina Niu  8
Affiliations
  • 1. State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 2. Department of Stomatology, Tangdu hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 3. Department of Cell Biology, National Translational Science Center for Molecular Medicine, The Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 4. Department of Radiotherapy, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 5. Catalan Institute for Research and Advanced Studies (ICREA), Passeig Luís Companys 23, Barcelona, Spain.
  • 6. BOBl-Bioinspired Oral Biomaterials and Interfaces, Department of Materials Science and Engineering, Barceloa East School of Engineering (EEBE), Universitat Politècnica de Catalunya-Barcelona Tech (UPC), C/. Eduard Maristany 16, Barcelona, Spain.
  • 7. The Dental College of Georgia, Augusta University, Augusta, GA, USA.
  • 8. State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, China. [email protected].
  • # Contributed equally.
PMID: 41361241 DOI: 10.1038/s41467-025-67214-5
Abstract

Ionizing radiation is effective in treating Cancer but causes significant damage to the mucosa, thereby increasing patient discomfort, delaying therapy, and raising the risk of mortality. The underlying mechanisms of this damage remain poorly understood, and current treatments are largely palliative. In this study, Ferroptosis was identified as the primary mode of cell death responsible for the radiation-induced depletion of oral mucosal epithelial cells. Notably, a compensatory phase was also discovered in the early stages following radiation exposure, during which fibroblasts provide crucial metabolic support. Specifically, fibroblasts supply polyamines that are readily absorbed by basal epithelial cells, protecting them from Ferroptosis. Supplementation with polyamines was found to effectively prevent mucosal injury. These findings highlight the critical role of fibroblast-mediated metabolic support in protecting the oral mucosa from radiation-induced damage and offer insights into enhancing the body's intrinsic protective mechanisms against radiation-related diseases.

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