Ethanolic Extract of Bupleurum Falcatum L. Root Attenuates Chronic Stress-Induced Cancer Metastasis via Inhibition of Src Kinase.

Psychological stress promotes cancer metastasis through activation of catecholamine-mediated β-adrenergic signaling. Bupleurum falcatum L. (BF) root has traditionally been used to treat stress-related disorders attributed to qi stagnation. This study investigated the anti-metastatic effects of an ethanolic extract of BF root (EBF) in chronic stress-induced cancer metastasis. EBF significantly suppressed adrenergic agonist-induced migration and invasion in MDA-MB-231 breast cancer and Hep3B hepatocellular carcinoma cells. In a chronic stress-induced lung metastasis mouse model, EBF markedly reduced lung metastasis of 4T1 breast cancer cells. Network pharmacology analysis and experimental validation identified Src as a key mediator of the anti-metastatic effects of EBF. Liquid chromatography-mass spectrometry (LC-MS) analysis confirmed the presence of major saikosaponins, and among them, saikosaponin D (SSD) showed notable inhibitory effects on cancer cell migration and Src phosphorylation. Molecular docking analysis further suggested a potential direct interaction between SSD and Src. These findings demonstrate that EBF attenuates chronic stress-induced cancer metastasis by inhibiting Src activation, supporting the traditional concept of soothing the liver and regulating qi as a therapeutic strategy for managing stress-related tumor progression.