Hepatic fibrosis is a woundhealing response for injury.Activated hepatic stellate cells (HSCs) are the preferred targets of antihepatic fibrotic therapies.Cucurbitacin E (CuE) is, one wellknown natural compound derived from Traditional Chinese Medicine, used in Asian countries for the prevention and treatment of hepatic disease.Therefore, the present study elucidated the mechanism of CuE on inducing apoptosis and attenuating hepatic fibrosis towards activated HSCs.The murine hepatic stellate cells (tHSC/Cl6) cell line were incubated in 96well plates and treated with TNFα and CuE at various concentrations and indicated times.Cell viability was assessed with MTT assay.Another, tHSC/Cl6 were incubated in 6well plates and also treated with TNFα, CuE, AICAR or metformin for the indicated time and concentration.Cell protein and mRNA were prepared using kit and relevant signaling were detected by Western blot and RTPCR.CuE inhibited cell proliferation of activated HSC/T6 cells in concentrationand timedependent manner.CuE triggered the activation of caspase3, cleaved the PARP, ration of bc12/bax, and cytochrom C protein in a timeand concentrationdependent manner.CuE decreased pErk/MAPK without effects on pp38 and pJNK.CuE inhibited the protein and mRNA expressions of αSMA, TIMP1 and collagen I in activated HSCT6.CuE broadly blocked pPI3K, pAkt, pmTOR and pp70S6K expressions.CuE significantly increased phosphorylated AMPK expression as well as AICAR and metoformin.And metformin showed significantly higher activation of AMPK than AICAR.Ability of CuE on activation of AMPK was between AICAR and metformin.Its also found that CuE significantly decreased pmTOR as well as AICAR and metformin.CuE could modulate HSC survival and activation as a potential antifibrotic agent for liver fibrosis treatment.The findings demonstrate that CuE induced HSC apoptosis via Erk/MAPK and PI3K/AktAMPKmTOR signaling.