Poor response to ionizing radiation (IR) due to resistance remains a clinical challenge. Altered metabolism represents a defining characteristic of nearly all types of cancers. However, how radio-resistance is linked to metabolic reprogramming remains elusive. The present study establishes a metabolic phenotype that mediates radiation resistance in hepatocellular carcinoma (HCC), whereby increased glucose flux leads to glucose addiction in radio-resistant HCC cells and a corresponding increase in glycerophospholipids biosynthesis to enhance the levels of cardiolipin. Accumulation of cardiolipin dampens the effectiveness of IR by inhibiting cytochrome c release to initiate apoptosis. We also demonstrate that mTORC1 signaling-mediated translational control of hypoxia inducible factor-1? (HIF-1?) and sterol regulatory element-binding protein-1 (SREBP1) remodels such metabolic cascade. Targeting mTORC1 or glucose to cardiolipin synthesis, in combination with IR, strongly diminishes tumor burden. Finally, activation of glucose metabolism predicts poor response to radiotherapy in cancer patients. Taken together, we uncover here a previously unrecognized link between radiation resistance and metabolic integration and suggest that metabolically dismantling the radio-resistant features of tumors may provide potential combination approaches for radiotherapy in HCC.