<scp>P53</scp> Competitively Binds <scp>P300</scp> to Suppress <scp>HIF</scp> ‐1α/ <scp>TFRC</scp> ‐Mediated Ferroptosis and Promote Doxorubicin Resistance in Breast Cancer

ABSTRACT Doxorubicin (DOX) resistance limits the efficacy of chemotherapy in breast cancer, and suppression of ferroptosis may contribute to this process. This study investigated the role of the Tumor Protein P53 (P53)/E1A‐associated protein P300 (P300)/Hypoxia‐inducible factor‐1α (HIF‐1α)/Transferrin Receptor (TFRC) axis in regulating ferroptosis and DOX resistance. Transcriptome sequencing and bioinformatics analyses were performed to identify ferroptosis‐related regulators associated with DOX resistance. Expression of P53, P300, HIF‐1α, and TFRC was assessed in clinical specimens and cell models using immunohistochemistry, Western blotting, and RT‐qPCR. A DOX‐resistant breast cancer cell model was established. Ferroptosis and DOX sensitivity were evaluated after modulation of P53, P300, and HIF‐1α. Co‐immunoprecipitation, dual‐luciferase reporter assays, ChIP‐qPCR, Re‐ChIP, and pharmacological inhibition were used to define the underlying mechanism. DOX‐resistant breast cancer tissues and MCF‐7/DOX cells showed reduced Fe 2+ , reactive oxygen species, and malondialdehyde levels, indicating impaired ferroptosis. P53 and P300 were upregulated, whereas HIF‐1α and its downstream iron uptake regulator TFRC were downregulated. P300 manipulation suggested that total P300 abundance alone did not determine HIF‐1α/TFRC activity. P53 overexpression suppressed HIF‐1α/TFRC signaling, reduced ferroptosis, and decreased DOX sensitivity, whereas P53 knockdown restored HIF‐1α/TFRC expression, promoted iron uptake and lipid peroxidation, and enhanced DOX responsiveness. Mechanistically, P53 competitively bound P300, limiting P300 availability for HIF‐1α and suppressing HIF‐1α/P300 co‐occupancy and transcriptional activation at the TFRC promoter. HIF‐1α knockdown or inhibition abolished the ferroptosis‐promoting and DOX‐sensitizing effects of P53 depletion. P53 promotes DOX resistance by suppressing HIF‐1α/P300‐mediated TFRC transcription and TFRC‐dependent ferroptosis, highlighting the P53/P300/HIF‐1α/TFRC axis as a potential therapeutic target in DOX‐resistant breast cancer.