Project Summary We hypothesize the existence of a p53-regulated nutrient-sensing metabolism checkpoint, in which dysregulation of key nutrients needed for oxidative metabolism drives accumulation of lipid peroxides. These lipid peroxides may enable activation of scavenging mechanisms that resolve the nutrient scarcity, induce alternative metabolic pathways that bypass the need for the scarce nutrients, and/or drive activation of ferroptotic cell death to eliminate cells damaged by nutrient scarcity. We suggest that each of these outputs can lead to a tumor suppressive phenotype, and that understanding the mechanisms that govern these processes is critical for understanding the evolution of human cancers and how they may be addressed with precision therapeutics. We focus here on the role of the p53 network in this checkpoint and its impact on tumor suppression. We have two major goals—to define how regulation of the mevalonate pathway by p53 alters sensitivity to ferroptosis in hepatocellular carcinomas and to define the regulatory mechanisms governing polyunsaturated fatty acid metabolism in lymphomas. Together, we suggest that these studies will define a critical new axis of p53-mediated tumor suppression and provide a new avenue for creation of precision cancer medicines.