We observed for the first time that plumbagin can significantly suppress the production of angiogenic cytokines (VEGF, bFGF, CTGF, and ET-1) and regulate the ANG1/2 balance when the SMMC-7721 were co-cultured with EA.hy926 cells or in the tumors in an orthotropic HCC mouse model. Here, CCN2 is linked to hepatocellular carcinoma.