Oroxin B (Hypocretin-2), one of flavonoids isolated from traditional Chinese herbal medicine Oroxylum indicum (L.) Vent, selectively induces tumor-suppressive ER stress in malignant lymphoma cells and has antioxidant activity. Oroxin B significantly inhibits proliferation and induce apoptosis, which may be strongly associated with the inhibiting COX-2/VEGF and PTEN/PI3K/AKT signaling pathway in SMMC-7721 cells, Oroxin B potentially be used as a novel therapeutic agent for liver cancer.COX-2, VEGF, PI3K, and p-AKT expression levels are downregulated, while PTEN is upregulated after Oroxin B treatment.