Nobiletin and polydatin synergistically alleviate triple-negative breast cancer liver metastasis via suppressing ECM1a-mediated fatty acid biosynthesis

Breast cancer liver metastasis (BCLM) is characterized by high incidence and poor prognosis, lacking effective therapeutic strategies. Recent evidence suggests that lipid metabolic reprogramming plays an important role in the initiation and development of BC metastasis. In clinical practice of traditional Chinese medicine, Citri Reticulatae Pericarpium-Reynoutria japonica Houtt. (CR) herb pair is used for the treatment of BCLM. In this study, we explored the active ingredients of CR herb pair and underlying mechanisms against BCLM. By RNA sequencing analysis, we showed that extracellular matrix protein 1 isoform a (ECM1a), a secreted multifunctional glycoprotein, was a vital link between liver-metastatic potential and fatty acid (FA)-biosynthesis program in triple-negative breast cancer (TNBC) cells. Through integrative screening approaches, nobiletin and polydatin were identified as the core active ingredients of the CR herb pair. As an ECM1a inhibitor, nobiletin+polydatin combination exerted superior synergistic inhibitory effects on TNBC cells and liver-metastatic xenograft models. We further revealed that nobiletin+polydatin combination impaired ECM1a-mediated tumor FA-biosynthesis program by downregulating PI3K/AKT/mTOR/SREBPs signaling. These results support nobiletin+polydatin combination as a novel and promising therapeutic option for BCLM and highlight the role of ECM1a as the targetable master regulator of lipid metabolism in BCLM.