Iron accumulation drives radiation-induced proctopathy via VDR/YAP signaling

Radiation proctopathy is a severe dose-limiting complication of pelvic radiotherapy that lacks effective interventions. Here, we investigate whether iron accumulation contributes to radiation-induced rectal fibrosis and elucidate the underlying mechanism. In a mouse model of radiation proctopathy, we observed significant ferritin-mediated iron accumulation in fibrotic rectal tissues, which was negatively correlated with vitamin D receptor (VDR) downregulation. In vitro, iron overload promoted activation of human and mouse rectal fibroblasts by suppressing VDR expression, which relieved inhibition of YAP and triggered its nuclear translocation, leading to upregulation of pro-fibrotic target genes (Ctgf and Ankrd1). Notably, treatment with the iron chelator deferoxamine (DFO) effectively cleared iron accumulation, restored VDR expression, inhibited YAP activation, and significantly alleviated radiation-induced collagen deposition and fibroblast activation in vivo. Collectively, these findings reveal a critical role of the 'iron accumulation-VDR-YAP' regulatory axis in radiation proctopathy and suggest that iron chelation represents a potential therapeutic strategy warranting further preclinical and clinical investigation.