Mutant p53 protects triple-negative breast adenocarcinomas from ferroptosis in vivo. The TP53 tumor suppressor gene is mutated early in most triple-negative breast cancer (TNBC) patients. Mutant p53 protects cells from ferroptosis, a cell death mechanism involving iron-dependent lipid peroxidation. In TNBCs, deletion of two different p53 mutants (p53R172H and p53R245W) triggers ferroptosis in vivo. Mutant p53 protects cells from ferroptosis inducers, and ferroptosis inhibitors reverse the effects of mutant p53 loss. Single-cell transcriptomic data revealed that mutant p53 protects cells from undergoing ferroptosis through NRF2-dependent regulation of Mgst3 and Prdx6, which encode two glutathione-dependent peroxidases that detoxify lipid peroxides. Thus, mutant p53 protects TNBCs from ferroptotic death. Mutant p53 protects breast adenocarcinomas from ferroptosis in vivo. The study used an autochthonous somatic TNBC mouse model with p53R172H and p53R245W mutations. Deletion of mutant Trp53 in these TNBCs caused tumor regression, cell death independent of apoptosis, and extended survival of mice. Downstream analyses revealed that deletion of mutant Trp53 activated the cGAS-STING pathway, indicating cell extrinsic effects, but did not cause apoptosis implicating other mechanisms of tumor regression. Thus, the study aimed to mechanistically examine dependencies on mutant p53 in these TNBCs. By using single-cell transcriptomics, the study found that mutant p53 mitigates oxidative stress and protects cells against ferroptosis through the NRF2-dependent regulation of Mgst3 and Prdx6. Mutant p53 protects breast adenocarcinomas from ferroptosis at GPX4 level. The study established cell lines from untreated breast tumors and used CRISPR to delete mutant Trp53. The clones with mutant Trp53 deletion were very sensitive to trypsinization, low cell density seeding, and increased acidity in the media requiring frequent changes of media. To directly assess the role of mutant p53 in ferroptosis, the study treated cells with RSL3, which induces ferroptosis by inhibiting GPX4. Mutant p53-deficient cells were more sensitive to RSL3-mediated cell death when compared to mutant p53 proficient ones. Liproxstatin-1 completely reversed RSL3-mediated cell death, indicating that the cells lacking mutant p53 indeed underwent ferroptosis upon RSL3 treatment. Similarly, the mutant p53-deficient cells were sensitive to two other inhibitors of GPXMutant p53 protects triple-negative breast adenocarcinomas from ferroptosis in vivo. The TP53 tumor suppressor gene is mutated early in most triple-negative breast cancer (TNBC) patients. Mutant p53 protects cells from ferroptosis, a cell death mechanism involving iron-dependent lipid peroxidation. In TNBCs, deletion of two different p53 mutants (p53R172H and p53R245W) triggers ferroptosis in vivo. Mutant p53 protects cells from ferroptosis inducers, and ferroptosis inhibitors reverse the effects of mutant p53 loss. Single-cell transcriptomic data revealed that mutant p53 protects cells from undergoing ferroptosis through NRF2-dependent regulation of Mgst3 and Prdx6, which encode two glutathione-dependent peroxidases that detoxify lipid peroxides. Thus, mutant p53 protects TNBCs from ferroptotic death. Mutant p53 protects breast adenocarcinomas from ferroptosis in vivo. The study used an autochthonous somatic TNBC mouse model with p53R172H and p53R245W mutations. Deletion of mutant Trp53 in these TNBCs caused tumor regression, cell death independent of apoptosis, and extended survival of mice. Downstream analyses revealed that deletion of mutant Trp53 activated the cGAS-STING pathway, indicating cell extrinsic effects, but did not cause apoptosis implicating other mechanisms of tumor regression. Thus, the study aimed to mechanistically examine dependencies on mutant p53 in these TNBCs. By using single-cell transcriptomics, the study found that mutant p53 mitigates oxidative stress and protects cells against ferroptosis through the NRF2-dependent regulation of Mgst3 and Prdx6. Mutant p53 protects breast adenocarcinomas from ferroptosis at GPX4 level. The study established cell lines from untreated breast tumors and used CRISPR to delete mutant Trp53. The clones with mutant Trp53 deletion were very sensitive to trypsinization, low cell density seeding, and increased acidity in the media requiring frequent changes of media. To directly assess the role of mutant p53 in ferroptosis, the study treated cells with RSL3, which induces ferroptosis by inhibiting GPX4. Mutant p53-deficient cells were more sensitive to RSL3-mediated cell death when compared to mutant p53 proficient ones. Liproxstatin-1 completely reversed RSL3-mediated cell death, indicating that the cells lacking mutant p53 indeed underwent ferroptosis upon RSL3 treatment. Similarly, the mutant p53-deficient cells were sensitive to two other inhibitors of GPX