Targeting lipid metabolism enzymes in breast cancer: Mechanistic basis and therapeutic vulnerabilities.

Breast cancer constitutes a metabolically heterogeneous disorder wherein enzymes associated with lipid metabolism are instrumental in tumor progression, adaptation to the microenvironment, and therapeutic response. Beyond their catalytic roles in fatty acid, cholesterol, and phospholipid metabolism, these enzymes may function as regulatory nodes linking lipid flux to membrane remodeling, lipid peroxide detoxification, autophagy-dependent recycling, epithelial-mesenchymal plasticity, tumor-macrophage crosstalk, epigenetic stabilization, and multidrug resistance (MDR). This review adopts a subtype-aware, node-based framework to analyze lipid metabolic enzymes as context-dependent drivers of malignant phenotypes and treatment resistance. Furthermore, pharmacological strategies targeting lipid metabolic pathways-including fatty acid synthase (FASN) inhibition, ferroptosis induction, blockade of fatty acid oxidation, modulation of cholesterol metabolism, and interference with lipid uptake-are examined. The majority of these strategies are currently at preclinical or early translational stages, encountering significant challenges such as toxicity, metabolic compensation, subtype heterogeneity, and inadequate biomarker-guided patient selection. This review emphasizes lipid-metabolism enzymes as potential therapeutic vulnerabilities and underscores the necessity for mechanistic validation, rational combination therapies, and biomarker-driven metabolic stratification in breast cancer.