The SLC7A11–ferroptosis axis in BRCA1-mutant breast cancer: current mechanistic evidence, potential therapeutic vulnerabilities, and translational perspectives
Abstract
BRCA1-mutant breast cancer is characterized by homologous recombination deficiency and genomic instability. Although these tumors are initially sensitive to platinum-based chemotherapy and PARP inhibitors, acquired treatment resistance remains a major clinical challenge. Ferroptosis is a potential therapeutic vulnerability, but the role of the SLC7A11/xCT–ferroptosis axis in this disease remains unclear. Current evidence does not establish whether increased SLC7A11 expression is a causal determinant of platinum- or PARP inhibitor resistance or a secondary response to treatment-induced stress; functional evidence directly linking SLC7A11 manipulation to drug resistance in genotype-defined BRCA1-mutant breast cancer remains limited. This review examines evidence linking SLC7A11-mediated cystine utilization to glutathione synthesis, GPX4-dependent antioxidant defense, redox and metabolic adaptation, and treatment response. We distinguish findings from BRCA1-mutant or BRCA1-deficient models from those in non-stratified breast cancer, TNBC, and broader cancer models, and discuss crosstalk with DNA damage responses and the tumor microenvironment. Individual studies have implicated VDAC3 in erastin response. BRCA1/BARD1-dependent GPX4 regulation has also been linked to ferroptosis control. However, these mechanisms require independent validation. Glucose restriction may produce overlapping but mechanistically separable ferroptotic and disulfidptotic phenotypes in SLC7A11-high cells; direct evidence for disulfidptosis in BRCA1-mutant breast cancer is lacking. Potential therapeutic strategies targeting SLC7A11, NRF2/ATF4 signaling, GPX4-related defenses, NADPH regeneration, glucose metabolism, and stromal or immune–metabolic interactions are reviewed. However, most SLC7A11-centered mechanistic and therapeutic evidence remains preclinical and has not been systematically validated in genotype-defined, platinum- or PARP inhibitor-resistant BRCA1-mutant breast cancer models. Future studies should prioritize biomarker-guided evaluation, pathway-selective experiments to distinguish ferroptosis from disulfidptosis, and prospective validation in treatment-resistant BRCA1-mutant models and clinical cohorts.
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BibTeX
@article{yang2026slc7a11ferroptosis,
title = {{The SLC7A11–ferroptosis axis in BRCA1-mutant breast cancer: current mechanistic evidence, potential therapeutic vulnerabilities, and translational perspectives}},
author = {Yuying Yang and Yu Li and Xiaoyu Hao and Wenwen Yan and Xiaodong Ma},
journal = {Frontiers in Oncology},
year = {2026},
month = oct,
doi = {10.3389/fonc.2026.1985224},
url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1985224},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The SLC7A11–ferroptosis axis in BRCA1-mutant breast cancer: current mechanistic evidence, potential therapeutic vulnerabilities, and translational perspectives
AU - Yuying Yang
AU - Yu Li
AU - Xiaoyu Hao
AU - Wenwen Yan
AU - Xiaodong Ma
PY - 2026
DA - 2026/10/30
JO - Frontiers in Oncology
DO - 10.3389/fonc.2026.1985224
UR - https://www.frontiersin.org/articles/10.3389/fonc.2026.1985224
AB - BRCA1-mutant breast cancer is characterized by homologous recombination deficiency and genomic instability. Although these tumors are initially sensitive to platinum-based chemotherapy and PARP inhibitors, acquired treatment resistance remains a major clinical challenge. Ferroptosis is a potential therapeutic vulnerability, but the role of the SLC7A11/xCT–ferroptosis axis in this disease remains unclear. Current evidence does not establish whether increased SLC7A11 expression is a causal determinant of platinum- or PARP inhibitor resistance or a secondary response to treatment-induced stress; functional evidence directly linking SLC7A11 manipulation to drug resistance in genotype-defined BRCA1-mutant breast cancer remains limited. This review examines evidence linking SLC7A11-mediated cystine utilization to glutathione synthesis, GPX4-dependent antioxidant defense, redox and metabolic adaptation, and treatment response. We distinguish findings from BRCA1-mutant or BRCA1-deficient models from those in non-stratified breast cancer, TNBC, and broader cancer models, and discuss crosstalk with DNA damage responses and the tumor microenvironment. Individual studies have implicated VDAC3 in erastin response. BRCA1/BARD1-dependent GPX4 regulation has also been linked to ferroptosis control. However, these mechanisms require independent validation. Glucose restriction may produce overlapping but mechanistically separable ferroptotic and disulfidptotic phenotypes in SLC7A11-high cells; direct evidence for disulfidptosis in BRCA1-mutant breast cancer is lacking. Potential therapeutic strategies targeting SLC7A11, NRF2/ATF4 signaling, GPX4-related defenses, NADPH regeneration, glucose metabolism, and stromal or immune–metabolic interactions are reviewed. However, most SLC7A11-centered mechanistic and therapeutic evidence remains preclinical and has not been systematically validated in genotype-defined, platinum- or PARP inhibitor-resistant BRCA1-mutant breast cancer models. Future studies should prioritize biomarker-guided evaluation, pathway-selective experiments to distinguish ferroptosis from disulfidptosis, and prospective validation in treatment-resistant BRCA1-mutant models and clinical cohorts.
SN - 2234-943X
ER -