Selective Radioprotection of Normal Cells by C60-ser via the Nrf2 Antioxidant Pathway

Abstract

Radiation-induced damage to normal tissues remains a major dose-limiting challenge in radiation oncology. [60]Fullerene (C60) is a potent antioxidant with the potential to reduce postradiotherapy normal tissue toxicity. Here, we demonstrate that a highly water-soluble C60 derivative, C60-ser, selectively protects normal cells from radiation-induced damage without altering the radiosensitivity of tumor cells in vitro and in vivo. C60-ser pretreatment markedly alleviated DNA damage, reduced cellular reactive oxygen species levels, and restored mitochondrial function upon irradiation. Remarkably, these radioprotective effects were confined to normal cells but not detected in cancer cells, highlighting the selective cytoprotective profile of C60-ser. Further, we identified the transcription factor Nrf2 as a mechanistic driver of C60-ser-mediated radioprotection. In normal cells, C60-ser activated the Nrf2 pathway by increasing the Nrf2 protein level and promoting its nuclear translocation. This resulted in the upregulation of downstream antioxidant genes including CAT (catalase). Pharmacological inhibition of Nrf2 or catalase impaired the C60-ser-induced antioxidant response, indicating a dependence on the Nrf2 antioxidant pathway. In contrast, C60-ser-pretreated cancer cells exhibited no change in Nrf2 protein levels or downstream gene induction, suggesting that the Nrf2 pathway is refractory to C60-ser in a malignant context. Collectively, our data establish that C60-ser is a radioprotectant selectively in normal cells through a redox-based mechanism to counteract radiotherapy-induced oxidative stress.