Abstract

Background Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) characterized by a high risk of metastasis and poor prognosis. Current chemotherapy-based treatments are often limited by systemic toxicity and drug resistance. Brusatol (BRU), a natural compound with reported anti-tumor activity and low toxicity, has not been explored in the context of cancer metastasis or metabolic reprogramming. This study aimed to uncover the anti-metastatic mechanism of BRU by targeting the metabolic adaptation of detached TNBC cells. Methods The suppressive effect of BRU was assessed via LDH release assays, trypan blue staining, tumor spheroid culture and spontaneous metastasis assays. To elucidate the underlying mechanisms, global metabolomics analysis, NADPH/NADP + measurements, intracellular ROS detection by flow cytometry, and quantitative PCR for metabolic gene expression were applied to evaluate metabolic alterations and redox imbalance. Results BRU promoted membrane damage and cell death in extracellular matrix (ECM)-detached TNBC cells and suppressed metastasis in vivo . Metabolomics analysis showed that BRU inhibited metabolic pathways, including the pentose phosphate pathway (PPP), glycolysis, and the tricarboxylic acid (TCA) cycle, while significantly reducing NADPH levels and exacerbating redox stress. Conclusions These findings suggest that BRU targets metabolic plasticity in TNBC cells, highlighting its potential as an adjuvant therapy to enhance anti-tumor efficacy while reducing chemotherapy-associated toxicity.