Frontiers in oncology · 2026
Ferroptosis in chemotherapy resistance and resensitization in breast cancer: a systematic review of preclinical evidence and translational implications.
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Shen Kezhen, Zhang Heng, Cai Lei
Аннотация
BACKGROUND: 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.
METHODS: 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 (in vivo) and adapted OHAT (in vitro) tools. A narrative synthesis and evidence strength ranking system (Levels A-C) were developed based on study number, in vivo validation, and drug class coverage.
RESULTS: Forty-four 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-study 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 in vivo validation. However, reporting of randomization (11.4%) and blinding (0%) in animal studies requires improvement.
CONCLUSION: 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.
SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420261334827.
METHODS: 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 (in vivo) and adapted OHAT (in vitro) tools. A narrative synthesis and evidence strength ranking system (Levels A-C) were developed based on study number, in vivo validation, and drug class coverage.
RESULTS: Forty-four 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-study 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 in vivo validation. However, reporting of randomization (11.4%) and blinding (0%) in animal studies requires improvement.
CONCLUSION: 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.
SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420261334827.