| Cannabinoids have been investigated in recent years for their ability to cause activated hepatic stellate cell (HSC) death, a proposed mechanism for regression of liver fibrosis. Here we demonstrate that cannabidiol, a major, non-psychoactive cannabinoid from the plant Cannabis sativa, induces apoptosis in activated HSCs through a cannabinoid receptor-independent mechanism. Cannabidiol elicits an endoplasmic reticulum (ER) stress response, characterized by initiation of PERK-, ATF6-, and IRE1-mediated signaling cascades, leading to downstream activation of the pro-apoptotic IRE1/ASK1/JNK pathway and HSC death. Furthermore, cannabidiol-induced ER stress-mediated apoptosis occurs specifically in activated HSC lines and primary in vivo-activated HSCs, but not in quiescent HSCs or hepatocytes. Finally, we provide evidence that the elevated basal level of ER stress in activated HSCs plays a role in susceptibility to the pro-apoptotic effect of cannabidiol. By selectively killing activated HSCs through ER stress-mediated apoptosis, cannabidiol may represent a novel approach for treating liver disease. |
