The study investigates the metabolic defects caused by the loss of matrix attachment in mammary epithelial cells and how these defects can be rescued. Detachment from the extracellular matrix (ECM) leads to an ATP deficiency due to reduced glucose transport. Overexpression of ErbB2 rescues this ATP deficiency by stabilizing EGFR and activating PI(3)K, which enhances glucose uptake through the pentose phosphate pathway (PPP). Interestingly, antioxidant treatment can also rescue the ATP deficiency by stimulating fatty acid oxidation (FAO), which is inhibited by reactive oxygen species (ROS) produced during detachment. The significance of these findings is supported by evidence of elevated ROS in matrix-deprived cells and the enhanced survival and anchorage-independent colony formation of these cells treated with antioxidants. These results highlight the importance of matrix attachment in regulating metabolic activity and suggest a novel mechanism for cell survival in altered matrix environments through antioxidant restoration of ATP generation.The study investigates the metabolic defects caused by the loss of matrix attachment in mammary epithelial cells and how these defects can be rescued. Detachment from the extracellular matrix (ECM) leads to an ATP deficiency due to reduced glucose transport. Overexpression of ErbB2 rescues this ATP deficiency by stabilizing EGFR and activating PI(3)K, which enhances glucose uptake through the pentose phosphate pathway (PPP). Interestingly, antioxidant treatment can also rescue the ATP deficiency by stimulating fatty acid oxidation (FAO), which is inhibited by reactive oxygen species (ROS) produced during detachment. The significance of these findings is supported by evidence of elevated ROS in matrix-deprived cells and the enhanced survival and anchorage-independent colony formation of these cells treated with antioxidants. These results highlight the importance of matrix attachment in regulating metabolic activity and suggest a novel mechanism for cell survival in altered matrix environments through antioxidant restoration of ATP generation.