The study investigates the role of p53 in tumor suppression through its regulation of cystine metabolism and ferroptosis. P53, a tumor suppressor protein, is known to induce cell-cycle arrest, senescence, and apoptosis, but recent studies suggest that its metabolic activities are also crucial. The authors found that p53 inhibits cystine uptake and sensitizes cells to ferroptosis, a non-apoptotic form of cell death, by repressing the expression of *SLC7A11*, a key component of the cystine/glutamate antiporter. Notably, the p53^3KR^ mutant, which lacks the ability to induce cell-cycle arrest, apoptosis, and senescence, still retains the ability to regulate *SLC7A11* expression and induce ferroptosis under reactive oxygen species (ROS)-induced stress. In mutant mice, these non-canonical p53 activities contribute to embryonic development and the lethality associated with loss of *Mdm2*. Overexpression of *SLC7A11* in human tumors inhibits ROS-induced ferroptosis and abrogates p53^3KR^-mediated tumor growth suppression in xenograft models. These findings uncover a new mode of tumor suppression based on p53 regulation of cystine metabolism, ROS responses, and ferroptosis.The study investigates the role of p53 in tumor suppression through its regulation of cystine metabolism and ferroptosis. P53, a tumor suppressor protein, is known to induce cell-cycle arrest, senescence, and apoptosis, but recent studies suggest that its metabolic activities are also crucial. The authors found that p53 inhibits cystine uptake and sensitizes cells to ferroptosis, a non-apoptotic form of cell death, by repressing the expression of *SLC7A11*, a key component of the cystine/glutamate antiporter. Notably, the p53^3KR^ mutant, which lacks the ability to induce cell-cycle arrest, apoptosis, and senescence, still retains the ability to regulate *SLC7A11* expression and induce ferroptosis under reactive oxygen species (ROS)-induced stress. In mutant mice, these non-canonical p53 activities contribute to embryonic development and the lethality associated with loss of *Mdm2*. Overexpression of *SLC7A11* in human tumors inhibits ROS-induced ferroptosis and abrogates p53^3KR^-mediated tumor growth suppression in xenograft models. These findings uncover a new mode of tumor suppression based on p53 regulation of cystine metabolism, ROS responses, and ferroptosis.