The role of ferroptosis in the pathogenesis and treatment of breast cancer

BACKGROUND: Breast cancer remains one of the most prevalent malignancies and a leading cause of cancer-related mortality among women worldwide. Despite significant advancements in therapeutic strategies, including surgery, radiotherapy, chemotherapy, and targeted therapy, challenges such as drug resistance, recurrence, and metastasis persist, underscoring the urgent need for novel treatment paradigms. Ferroptosis, a newly characterized form of regulated cell death driven by iron-dependent lipid peroxidation, has emerged as a critical player in tumor biology. Its distinct mechanistic features and regulatory networks offer promising avenues for overcoming therapy resistance and improving clinical outcomes in breast cancer. MAIN BODY: Ferroptosis is orchestrated by a complex interplay of metabolic and signaling pathways, primarily involving lipid peroxidation of polyunsaturated fatty acids (PUFAs), iron accumulation, and dysfunction of antioxidant systems such as the System Xc⁻/glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis, as well as non-canonical pathways including FSP1-CoQ₁₀ and DHODH-CoQH₂. These pathways are intricately regulated by transcription factors (e.g., p53, NRF2, ATF3), epigenetic modifiers, and non-coding RNAs, linking ferroptosis to key cellular processes such as energy metabolism, redox homeostasis, and immune modulation. In breast cancer, ferroptosis plays a dual role in tumor suppression and immune regulation. It influences cancer stem cell maintenance, epithelial-mesenchymal transition (EMT), and the tumor microenvironment (TME) by modulating immune cell functions, including CD8⁺ T cells, tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs). Notably, ferroptosis induction has been shown to enhance the efficacy of conventional therapies (e.g., chemotherapy, radiotherapy, and immunotherapy) and reverse drug resistance in various breast cancer subtypes, particularly triple-negative breast cancer (TNBC). Emerging evidence highlights the therapeutic potential of small-molecule inducers, natural compounds, and nanomedicines that target key ferroptosis regulators such as GPX4, ACSL4, SLC7A11, FSP1, and DHODH. Moreover, ferroptosis-related gene signatures have been increasingly utilized to construct prognostic models and predict therapeutic responses in breast cancer patients. CONCLUSION: Ferroptosis represents a pivotal mechanism in the pathogenesis and therapeutic response of breast cancer. Targeting ferroptosis pathways offers a promising strategy to enhance treatment sensitivity, overcome drug resistance, and improve patient prognosis. Future research should focus on elucidating the precise molecular mechanisms governing ferroptosis in distinct breast cancer subtypes, developing highly specific and safe ferroptosis-inducing agents, and optimizing combination regimens with existing immunotherapies and targeted therapies to facilitate clinical translation.