Metabolic Regulation of Ferroptosis in Breast Cancer.

Breast cancer, a leading global malignancy, exhibits extensive metabolic reprogramming that drives tumorigenesis, therapy resistance, and survival. Ferroptosis, an iron-dependent regulated cell death mechanism characterized by lipid peroxidation, emerges as a promising therapeutic vulnerability, particularly in aggressive subtypes like triple-negative breast cancer (TNBC). This literature review comprehensively explores the metabolic regulation of ferroptosis in breast cancer cells, focusing on how dysregulated pathways modulate sensitivity or resistance. The review will discuss iron homeostasis, including upregulated transferrin receptor 1 (TFR1), diminished ferroportin, mitochondrial dynamics, and ferritinophagy, which catalyze ROS via Fenton reactions. It will examine glutathione (GSH) metabolism through the GPX4-GSH axis, with subtype-specific reliance on cystine import via xCT or de novo cysteine synthesis. Lipid metabolism will be analyzed as the core battleground, highlighting polyunsaturated fatty acid (PUFA) incorporation by ACSL4 promoting peroxidation, contrasted with monounsaturated fatty acid (MUFA) protection via SCD1, alongside subtype adaptations. Further, the review will address tumor microenvironment influences, such as cysteine supply from cancer-associated fibroblasts and oleic acid from adipocytes. Oncogenic signaling (e.g., RAS, mTOR) and tumor suppressors (e.g., p53) will be evaluated for their roles in resistance or sensitivity. Intersections with glucose metabolism (Warburg effect) and selenium-dependent antioxidants will be explored. Therapeutically, the review will consider targeting these nodes with GPX4 inhibitors or iron overload, synergized with immunotherapy for immunogenic cell death. Future directions will emphasize multi-omics integration and patient-derived organoids to uncover subtype-specific strategies for precision medicine in breast cancer.