Ferroptosis in Breast Cancer: Molecular Insights and Therapeutic Strategies

Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation and insufficient antioxidant defenses and is mechanistically distinct from apoptosis, necroptosis, and other cell death mechanisms. Over the past decade, ferroptosis has emerged as a significant determinant of cancer cell fate. An increasing body of research indicates that it may serve as a vulnerability in breast cancer treatment. Breast cancers undergo significant metabolic and redox reprogramming that directly influences ferroptosis regulation, including alterations in iron homeostasis, polyunsaturated lipid metabolism, and antioxidant networks. Sensitivity to ferroptosis varies among breast cancer subtypes, underscoring subtype-specific metabolic requirements and stress-response mechanisms. Ferroptosis plays a critical role in breast cancer stem cells (BCSCs), therapeutic resistance, and tumor recurrence. Targeting ferroptosis provides a promising therapeutic strategy to eradicate drug-resistant, stem-like populations. Ferroptosis also profoundly influences the tumor microenvironment (TME) by altering immune cell function, reshaping stromal cell interactions, and modulating cellular responses to hypoxia and metabolic stress. This review summarizes the current mechanistic insights into ferroptosis regulation in breast cancer and discusses therapeutic avenues targeting breast cancer cells, stem cells, and the tumor microenvironment. Understanding ferroptosis mechanisms in breast cancer subtypes may enable rational, biomarker-guided strategies to overcome therapeutic resistance and improve clinical outcomes for patients with breast cancer.