Role of ferroptosis in breast cancer: Molecular mechanisms and therapeutic interventions

Ferroptosis, an iron-dependent cell death pathway distinct from apoptosis, is crucial in breast cancer (BC) research, especially for overcoming resistance in triple-negative breast cancer (TNBC). Unlike traditional apoptosis, ferroptosis involves the glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis, iron-driven oxidative reactions, and phospholipid peroxidation. TNBC, characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), is particularly prone to ferroptosis due to acyl-coenzyme A synthetase (ACSL) 4-related lipid changes and solute carrier family 7 member 11 (SLC7A11)-mediated cystine transport. Recent advancements in biomarkers and therapeutic strategies targeting ferroptosis hold significant promise for the diagnosis and prognosis of TNBC. Notable innovations encompass the development of small-molecule compounds and various methodologies designed to enhance ferroptosis. Combination therapies have demonstrated improved antitumor efficacy by counteracting chemotherapy resistance and inducing immunogenic cell death. Nonetheless, challenges persist in optimizing drug delivery mechanisms and minimizing off-target effects. This review underscores the progress in ferroptosis research and proposes precision oncology strategies that exploit metabolic flexibility in BC, intending to transform TNBC treatment and enhance therapeutic outcomes.