It has been reported that calpain/caspase-mediated apoptosis induced by endoplasmic reticulum stress (ERS) in hepatic stellate cells (HSCs) by previous studies. At present, the activation of HSC is an important cause of liver fibrosis, and the induction of HSC apoptosis plays an irreplaceable role in reversing liver fibrosis. Therefore, it is of great significance to explore mechanisms of action that can induce HSC apoptosis for the reversal of hepatic fibrosis and the clinical prevention and treatment of hepatic-fibrosis-related diseases such as hepatitis, cirrhosis, and liver cancer. In the current study, we demonstrated that tunicamycin (a novel ERS inducer) can induce the apoptosis of HSCs and increase the concentration of intracellular Ca2+ and the expression of ERS protein GRP78, apoptosis protein caspase-12, and Bax, while it can decrease the antiapoptosis protein expression of Bcl-2. Our findings indicate that tunicamycin can induce HSCs apoptosis through calpain-2/Ca2+-dependent ERS pathway.

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Activated hepatic stellate cell (HSC) is the central link to the occurrence and development of liver fibrosis, which can be reversed by promoting the apoptosis of HSC. The activation of HSC leads to an increase in proliferation, collagen synthesis and the contraction of HSCs. The studies in vitro and in vivo have shown that intracellular Ca2+ plays an important role in the mediating apoptosis and contraction of HSC. The phosphatidyl inositol 3-kinase (PI3K)/Akt signalling pathway is closely related to the occurrence and development of liver fibrosis. In this study, we investigated the effect of PI3K inhibitor PI103 on HSC stimulated by transforming growth factor-β1(TGF-β1) and explored its relevant mechanisms. The results showed PI3K inhibitor PI103 could inhibit the proliferation of activated HSC, increase its apoptosis, decrease intracellular Ca2+ concentration and reduce the expression of signal molecules PI3K and Akt and type I, III collagen as well. Our study demonstrates that Ca2+ and PI3K/Akt-dependent HSC apoptosis may serve as a potential novel target for anti-fibrosis therapy.