Metabolic support protects mucosa from ferroptosis in radiation-induced mucositis

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.