OBJECTIVE:To investigate the possible molecular mechanism of total glycosides of Chishao (Radix Paeoniae Rubra) (TG-RPR) on proliferation and apoptosis of hepatocellular carcinoma cells.METHODS:The proliferation of TG-RPR on HepG2 cells was detected using the 3-(4,5-Dimethylthia-zol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) as-say.The apoptosis of HepG2 cells was measured by annexin V-FITC/double staining.The phosphatase and tensin homolog deleted on chromosome ten(PTEN)/phosphatidylinositol 3-kinase (PI3K)/pro-tein kinase B (Akt) signaling pathway was evaluat-ed by Western Blot and reverse transcription-poly-merase chain reaction (RT-PCR).RESULTS:TG-RPR can up-regulation the expression of pro-apoptotic factors such as PTEN and BCL2-As-sociated X (Bax),down-regulation the expression of anti-apoptotic factors including B-cell lymphoma-2(Bcl-2),PI3K,and Akt.CONCLUSION:TG-RPR significantly inhibits the pro-liferation of HepG2 cells in a dose-dependent manner and promotes apoptosis.These results demonstrated TG-RPR has significant inhibitory ef-fect on HepG2 cells.These results identify a critical role of TG-RPR in proliferation and apoptosis of HepG2 cells via modulating PTEN/PI3K/Akt signal-ing pathway.TG-RPR may offer a promise as a po-tential pharmaceutical therapy for hepatocellular carcinoma.