AdipoR1 Regulates Ionizing Radiation-Induced Ferroptosis in HCC Cells Through Nrf2/xCT Pathway

Abstract Background: Ferroptosis is a type of cell death accompanied by iron-dependent lipid peroxidation, however, how IR-induced ferroptosis is regulated in Hepatocellular carcinoma cells (HCC) remains largely unknown. We have previously found that adiponectin receptor 1(AdipoR1) might be a prognostic biomarker for HCC after stereotactic body radiotherapy (SBRT). In this study, we aimed to elucidate the roles of AdipoR1 in radiation-induced Ferroptosis of HCC.Methods: Human HCC cell line MHCC-97H and HepG2 and human hepatic cell lines LO2 were tested. qRT-PCR and western blotting were used to detect mRNA and protein expression respectively, colony formation assay was used to evaluate the radiosensitivity and flow cytometry was used to assess lipid peroxidation and cell death. Dual-Luciferase Reporter assay system was used to detect the transcription activity. Results: Ionizing Radiation (IR) upregulated the expression of AdipoR1 in HCC cells and AdipoR1 knockdown could promote radiation sensitivity of HCC cells. AdipoR1 knockdown could decrease the expression of Nrf2 and Nrf2 protein stability. Nrf2 could bind to xCT promoter and promoted the transcription and expression of xCT. AdipoR1 knockdown increased significantly lipid peroxidation and ferroptosis induced by IR or Erastin respectively, which could be abolished by overexpression of Nrf2 and xCT.Conclusion: AdipoR1 knockdown can promote radiation sensitivity of HCC cells; AdipoR1 regulates IR-induced cell death by AdipoR1-Nrf2-xCT pathway.