Artesunate induces ER-derived-ROS-mediated cell death by disrupting labile iron pool and iron redistribution in hepatocellular carcinoma cells

Aberrant iron homeostasis is a typical characteristic of Hepatocellular carcinoma (HCC), and perturbation of iron metabolism is an effective strategy for HCC therapy. However, there are few safe and effective targeting agents available in clinical practices. The artemisinin and its derivatives have shown potential anti-cancer activity by disturbing cellular iron homeostasis, but the specific mechanism is still unclear. In this study, we demonstrate that Artesunate (ART), a water-soluble anti-malaria agent in clinical use, can regulate the labile iron pool (LIP) and effectively induce ROS-dependent cell death in multiple HCC cells. Mechanistically, ART increases the LIP by promoting lysosomal degradation of iron-storage protein ferritin through acidizing lysosomes. Then the accumulation of labile iron in the endoplasmic reticulum (ER) promotes excessive Reactive Oxygen Species (ROS) production and severe ER disruption, which leads to cell death. Our results provide a new understanding of how ART modulates iron metabolism in HCC cells at the subcellular level, demonstrate the significance of endoplasmic reticulum as iron-vulnerability of HCC cells. More importantly, our findings suggest ART is a safe and potential anti-HCC agent via disturbing iron homeostasis.