The study investigates the role of mutant p53 in protecting triple-negative breast adenocarcinomas (TNBCs) from ferroptosis, a form of iron-dependent lipid peroxidation-mediated cell death. Using an autochthonous somatic TNBC mouse model, researchers toggled the expression of mutant p53 on and off while maintaining a wild-type tumor microenvironment. They found that deletion of two different hotspot p53 mutants, p53R172H and p53R245W, triggers ferroptosis in vivo. Mutant p53 protects cells from ferroptosis by regulating the expression of *Mgst3* and *Prdx6*, two glutathione-dependent peroxidases that detoxify lipid peroxides. Single-cell transcriptomic analysis revealed that mutant p53 mitigates oxidative stress and protects cells from ferroptosis through NRF2-dependent regulation of these genes. In human TNBC cell lines, silencing of mutant p53 also decreased the levels of *MGST3* and *PRDX6*, increasing sensitivity to ferroptosis. The study highlights the potential of targeting mutant p53 and the NRF2 pathway as a therapeutic strategy for TNBCs.The study investigates the role of mutant p53 in protecting triple-negative breast adenocarcinomas (TNBCs) from ferroptosis, a form of iron-dependent lipid peroxidation-mediated cell death. Using an autochthonous somatic TNBC mouse model, researchers toggled the expression of mutant p53 on and off while maintaining a wild-type tumor microenvironment. They found that deletion of two different hotspot p53 mutants, p53R172H and p53R245W, triggers ferroptosis in vivo. Mutant p53 protects cells from ferroptosis by regulating the expression of *Mgst3* and *Prdx6*, two glutathione-dependent peroxidases that detoxify lipid peroxides. Single-cell transcriptomic analysis revealed that mutant p53 mitigates oxidative stress and protects cells from ferroptosis through NRF2-dependent regulation of these genes. In human TNBC cell lines, silencing of mutant p53 also decreased the levels of *MGST3* and *PRDX6*, increasing sensitivity to ferroptosis. The study highlights the potential of targeting mutant p53 and the NRF2 pathway as a therapeutic strategy for TNBCs.