{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T09:51:06Z","timestamp":1782899466632,"version":"3.54.5"},"reference-count":81,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Chemotherapy resistance remains a major obstacle in breast cancer treatment, particularly in triple-negative breast cancer (TNBC). Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a potential therapeutic vulnerability in drug-resistant cancers, but preclinical evidence lacks systematic synthesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      PubMed, Scopus, Embase and Web of Science were systematically searched for original studies published between January 2016 and May 2026 investigating ferroptosis in chemotherapy-resistant breast cancer models. Study characteristics, mechanistic data, and outcomes were extracted. Methodological quality was assessed using SYRCLE (\n                      <jats:italic>in vivo<\/jats:italic>\n                      ) and adapted OHAT (\n                      <jats:italic>in vitro<\/jats:italic>\n                      ) tools. A narrative synthesis and evidence strength ranking system (Levels A-C) were developed based on study number,\n                      <jats:italic>in vivo<\/jats:italic>\n                      validation, and drug class coverage.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Forty\u2212four studies met inclusion criteria, with the majority published since 2024. TNBC was the focus of 47.7% of studies. Mechanisms were classified into six categories: GPX4 axis (28 studies, 63.6%), iron metabolism regulation (8 studies, 18.2%), SLC7A11\/xCT pathway (5 studies, 11.4%), and three single\u2212study mechanisms (6.8% combined). GPX4 modulation demonstrated efficacy across all drug classes. Evidence ranking classified the GPX4 axis, iron metabolism regulation, and the SLC7A11\/xCT pathway as Level A (strong evidence), and the remaining mechanisms as Level C. Methodological quality was adequate: 88.6% performed rescue experiments, 79.5% included\n                      <jats:italic>in vivo<\/jats:italic>\n                      validation. However, reporting of randomization (11.4%) and blinding (0%) in animal studies requires improvement.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Ferroptosis regulation represents a mechanistically diverse and promising strategy to overcome breast cancer chemoresistance. The GPX4 axis, iron metabolism regulation, and the SLC7A11\/xCT pathway are the most consistently supported mechanisms, providing a framework for prioritizing translational targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic Review Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/PROSPERO\/<\/jats:ext-link>\n                      , identifier CRD420261334827.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1854602","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T09:34:13Z","timestamp":1782898453000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Ferroptosis in chemotherapy resistance and resensitization in breast cancer: a systematic review of preclinical evidence and translational implications"],"prefix":"10.3389","volume":"16","author":[{"given":"Kezhen","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Breast and Thyroid Surgery, Third Xiangya Hospital, Central South University","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Fujian Medical University","place":["Fuzhou, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery, Third Xiangya Hospital, Central South University","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence 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