{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T09:23:57Z","timestamp":1787822637648,"version":"build-2784847793"},"reference-count":42,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82072909"],"award-info":[{"award-number":["82072909"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2026,8,31]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    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\u2010associated protein P300 (P300)\/Hypoxia\u2010inducible factor\u20101\u03b1 (HIF\u20101\u03b1)\/Transferrin Receptor (TFRC) axis in regulating ferroptosis and DOX resistance. Transcriptome sequencing and bioinformatics analyses were performed to identify ferroptosis\u2010related regulators associated with DOX resistance. Expression of P53, P300, HIF\u20101\u03b1, and TFRC was assessed in clinical specimens and cell models using immunohistochemistry, Western blotting, and RT\u2010qPCR. A DOX\u2010resistant breast cancer cell model was established. Ferroptosis and DOX sensitivity were evaluated after modulation of P53, P300, and HIF\u20101\u03b1. Co\u2010immunoprecipitation, dual\u2010luciferase reporter assays, ChIP\u2010qPCR, Re\u2010ChIP, and pharmacological inhibition were used to define the underlying mechanism. DOX\u2010resistant breast cancer tissues and MCF\u20107\/DOX cells showed reduced Fe\n                    <jats:sup>2+<\/jats:sup>\n                    , reactive oxygen species, and malondialdehyde levels, indicating impaired ferroptosis. P53 and P300 were upregulated, whereas HIF\u20101\u03b1 and its downstream iron uptake regulator TFRC were downregulated. P300 manipulation suggested that total P300 abundance alone did not determine HIF\u20101\u03b1\/TFRC activity. P53 overexpression suppressed HIF\u20101\u03b1\/TFRC signaling, reduced ferroptosis, and decreased DOX sensitivity, whereas P53 knockdown restored HIF\u20101\u03b1\/TFRC expression, promoted iron uptake and lipid peroxidation, and enhanced DOX responsiveness. Mechanistically, P53 competitively bound P300, limiting P300 availability for HIF\u20101\u03b1 and suppressing HIF\u20101\u03b1\/P300 co\u2010occupancy and transcriptional activation at the TFRC promoter. HIF\u20101\u03b1 knockdown or inhibition abolished the ferroptosis\u2010promoting and DOX\u2010sensitizing effects of P53 depletion. P53 promotes DOX resistance by suppressing HIF\u20101\u03b1\/P300\u2010mediated TFRC transcription and TFRC\u2010dependent ferroptosis, highlighting the P53\/P300\/HIF\u20101\u03b1\/TFRC axis as a potential therapeutic target in DOX\u2010resistant breast cancer.\n                  <\/jats:p>","DOI":"10.1096\/fj.202602247r","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T10:35:56Z","timestamp":1787049356000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>P53<\/scp>\n                    Competitively Binds\n                    <scp>P300<\/scp>\n                    to Suppress\n                    <scp>HIF<\/scp>\n                    \u20101\u03b1\/\n                    <scp>TFRC<\/scp>\n                    \u2010Mediated Ferroptosis and Promote Doxorubicin Resistance in Breast Cancer"],"prefix":"10.1096","volume":"40","author":[{"given":"Xiaojie","family":"Yu","sequence":"first","affiliation":[{"name":"Department of General Surgery Northern Jiangsu People's Hospital Affiliated to Yangzhou University  Yangzhou Jiangsu P.R. 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of General Surgery Northern Jiangsu People's Hospital Affiliated to Yangzhou University  Yangzhou Jiangsu P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6877-6864","authenticated-orcid":false,"given":"Deyuan","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of General Surgery Northern Jiangsu People's Hospital Affiliated to Yangzhou University  Yangzhou Jiangsu P.R. 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