The p53 tumor suppressor has been shown to protect the genome from oxidative damage caused by reactive oxygen species (ROS), in addition to its well-known roles in growth arrest and apoptosis. This study demonstrates that p53 regulates antioxidant genes, reducing intracellular ROS levels and preventing DNA oxidation, mutations, and karyotype instability. In the absence of severe stress, low levels of p53 are sufficient to up-regulate antioxidant genes, which decrease ROS. Conversely, down-regulation of p53 leads to increased ROS, DNA oxidation, and mutations, which are mitigated by antioxidant treatment with N-acetylcysteine (NAC). Dietary NAC supplementation prevents lymphomas in p53 knockout mice and slows the growth of xenografts from A549 cells with inhibited p53. These findings suggest that p53 has a non-restrictive antioxidant function, which is crucial for maintaining genetic stability and preventing cancer. The study reveals that p53 has both pro-oxidant and antioxidant functions, depending on the cellular context. While some p53-regulated genes contribute to pro-oxidant effects, others, such as sestrins, act as antioxidants. The antioxidant function of p53 is mediated through the up-regulation of antioxidant genes, which are responsive to lower levels of p53 in non-stressed or physiologically-stressed cells. The pro-oxidant function of p53 is linked to the release of mitochondrial ROS during stress-induced apoptosis. These findings highlight the dual role of p53 in ROS regulation and its importance in maintaining genetic stability. The study also shows that p53 deficiency leads to increased intracellular ROS, DNA oxidation, and mutagenesis, which contribute to the development of tumors. In p53-deficient mice, NAC supplementation significantly reduces tumor incidence, particularly thymic lymphomas, and improves genetic stability. These results suggest that antioxidants like NAC could be effective in cancer prevention and treatment, especially in individuals with inherited p53 deficiencies. The study further demonstrates that p53 deficiency promotes the growth of xenografts and increases the risk of lymphomas. NAC supplementation significantly reduces tumor growth in p53-deficient cells, indicating that antioxidants may be beneficial in cancer therapy. The findings underscore the importance of p53 in maintaining genetic stability and the potential of antioxidants in cancer prevention and treatment.The p53 tumor suppressor has been shown to protect the genome from oxidative damage caused by reactive oxygen species (ROS), in addition to its well-known roles in growth arrest and apoptosis. This study demonstrates that p53 regulates antioxidant genes, reducing intracellular ROS levels and preventing DNA oxidation, mutations, and karyotype instability. In the absence of severe stress, low levels of p53 are sufficient to up-regulate antioxidant genes, which decrease ROS. Conversely, down-regulation of p53 leads to increased ROS, DNA oxidation, and mutations, which are mitigated by antioxidant treatment with N-acetylcysteine (NAC). Dietary NAC supplementation prevents lymphomas in p53 knockout mice and slows the growth of xenografts from A549 cells with inhibited p53. These findings suggest that p53 has a non-restrictive antioxidant function, which is crucial for maintaining genetic stability and preventing cancer. The study reveals that p53 has both pro-oxidant and antioxidant functions, depending on the cellular context. While some p53-regulated genes contribute to pro-oxidant effects, others, such as sestrins, act as antioxidants. The antioxidant function of p53 is mediated through the up-regulation of antioxidant genes, which are responsive to lower levels of p53 in non-stressed or physiologically-stressed cells. The pro-oxidant function of p53 is linked to the release of mitochondrial ROS during stress-induced apoptosis. These findings highlight the dual role of p53 in ROS regulation and its importance in maintaining genetic stability. The study also shows that p53 deficiency leads to increased intracellular ROS, DNA oxidation, and mutagenesis, which contribute to the development of tumors. In p53-deficient mice, NAC supplementation significantly reduces tumor incidence, particularly thymic lymphomas, and improves genetic stability. These results suggest that antioxidants like NAC could be effective in cancer prevention and treatment, especially in individuals with inherited p53 deficiencies. The study further demonstrates that p53 deficiency promotes the growth of xenografts and increases the risk of lymphomas. NAC supplementation significantly reduces tumor growth in p53-deficient cells, indicating that antioxidants may be beneficial in cancer therapy. The findings underscore the importance of p53 in maintaining genetic stability and the potential of antioxidants in cancer prevention and treatment.