AdipoR1 Regulates Ionizing Radiation-Induced Ferroptosis in HCC cells through Nrf2/xCT Pathway

Radiotherapy has been used for decades in the treatment of liver cancer. We previously found that adiponectin receptor (AdipoR1) is a prognostic biomarker for hepatoma carcinoma (HCC) after stereotactic body radiation therapy (SBRT) and blocking AdipoR1 enhances radiation sensitivity in hepatoma carcinoma cells. In the current study, we aimed to elucidate the roles of AdipoR1 in ionizing radiation- (IR-) induced radiosensitivity by activating ferroptosis pathway in HCC cells. We found that IR upregulated the expression of AdipoR1 and furthermore promoted the protein stability of transcription factor Nrf2, Nrf2 binded to the xCT promoter and increased xCT transcription and expression, and this directly contributed to the protective function in the early stage of radiation in HCC cells. AdipoR1 knockdown significantly inhibited expression of Nrf2 and xCT and, furthermore, increased both IR- and erastin-induced ferroptosis, which could be abolished by the rescue of Nrf2 and xCT. For the first time, we found that radiation-induced ferroptosis was mediated by AdipoR1-Nrf2-xCT pathway in HCC cells. These results provide new insights to the development and application of novel therapeutic strategies for hepatoma carcinoma.