<p>Ferroptosis, a regulated form of cell death characterized by iron accumulation and lipid peroxidation, has gained increasing attention as a therapeutic target in cancer. Polyethylene glycol–liposomal doxorubicin (PLD), a nanocarrier formulation with improved pharmacological properties, shows promise in breast cancer therapy, yet the molecular mechanisms underlying its effects on ferroptosis remain unclear. Breast cancer cell lines (MDA-MB-231 and MCF-7) were treated with PLD to evaluate its anti-tumor effects. Cell viability, colony formation, and migration assays were performed, while lipid ROS accumulation was assessed using BODIPY-C11, and oxidative stress markers (MDA, Fe, GSH, and SOD) were quantified. Western blotting and immunofluorescence were used to examine NRF2/xCT/GPX4 signaling, and molecular docking predicted the interactions of PLD with KEAP1 and NRF2. Functional roles were further validated through NRF2 overexpression and KEAP1-R483S mutation. PLD exerts potent anti-breast cancer effects by suppressing cell viability, colony formation, and migration in MDA-MB-231 and MCF-7 cells. Mechanistically, PLD induces ferroptosis, evidenced by increased lipid ROS, elevated MDA and Fe levels, decreased GSH content and SOD activity, and downregulation of xCT and GPX4. NRF2 overexpression attenuates these effects by restoring antioxidant defenses, reducing lipid peroxidation and iron accumulation, and partially rescuing cell proliferation and migration. Molecular docking further revealed stable interactions of PLD with KEAP1 and NRF2, with Arg483 identified as a key residue mediating KEAP1–NRF2 and PLD–KEAP1 binding, suggesting that KEAP1 modulates NRF2 stability and cellular susceptibility to ferroptosis. Collectively, these results indicate that PLD partially inhibits breast cancer growth through KEAP1/NRF2-mediated ferroptosis, highlighting a novel mechanism underlying its anti-tumor activity.</p>