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.

Radiation liver injury is a common complication of hepatocellular carcinoma radiotherapy. It is mainly caused by irreversible damage to the DNA of hepatocellular cells directly by radiation, which seriously interferes with metabolism and causes cell death. AdipoRon can maintain lipid metabolism and stabilize blood sugar by activating adiponectin receptor 1 (AdipoR1). However, the role of AdipoRon/AdipoR1 in the regulation of ionizing radiation (IR)-induced mitochondrial damage remains unclear. In this study, we aimed to elucidate the roles of AdipoRon/AdipoR1 in IR-induced mitochondrial damage in normal hepatocyte cells. We found that AdipoRon treatment rescued IR-induced liver damage in mice and mitochondrial damage in normal hepatocytes in vivo and in vitro. AdipoR1 deficiency exacerbated IR-induced oxidative stress, mitochondrial dynamics, and biogenesis disorder. Mechanistically, the absence of AdipoR1 inhibits the activity of adenosine monophosphate-activated protein kinase α (AMPKα), subsequently leading to disrupted mitochondrial dynamics by decreasing mitofusin (MFN) and increasing dynamin-related protein 1 (DRP1) protein expression. It also controls mitochondrial biogenesis by suppressing the peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC1α) and transcription factor A (TFAM) signaling pathway, ultimately resulting in impaired mitochondrial function. To sum up, AdipoRon/AdipoR1 maintain mitochondrial function by regulating mitochondrial dynamics and biogenesis through the AdipoR1-AMPKα signaling pathway. This study reveals the significant role of AdipoR1 in regulating IR-induced mitochondrial damage in hepatocytes and offers a novel approach to protecting against damage caused by IR.