Sigma-1 receptor protects against ferroptosis in hepatocellular carcinoma cells.

Sigma-1 receptor (S1R) regulates reactive oxygen species (ROS) accumulation via nuclear factor erythroid 2-related factor 2 (NRF2), which plays a vital role in ferroptosis. Sorafenib is a strong inducer of ferroptosis but not of apoptosis. However, the mechanism of sorafenib-induced ferroptosis in hepatocellular carcinoma (HCC) remains unclear. In this study, we found for the first time that sorafenib induced most of S1Rs away from nucleus compared to control groups in Huh-7 cells, and ferrostatin-1 completely blocked the translocation. S1R protein expression, but not mRNA expression, in HCC cells was significantly up-regulated by sorafenib. Knockdown of NRF2, but not of p53 or hypoxia-inducible factor 1-alpha (HIF1α), markedly induced S1R mRNA expression in HCC cells. Inhibition of S1R (by RNAi or antagonists) increased sorafenib-induced HCC cell death in vitro and in vivo. Knockdown of S1R blocked the expression of glutathione peroxidase 4 (GPX4), one of the core targets of ferroptosis, in vitro and in vivo. Iron metabolism and lipid peroxidation increased in the S1R knockdown groups treated with sorafenib compared to the control counterpart. Ferritin heavy chain 1 (FTH1) and transferrin receotor protein 1 (TFR1), both of which are critical for iron metabolism, were markedly up-regulated in HCC cells treated with erastin and sorafenib, whereas knockdown of S1R inhibited these increases. In conclusion, we demonstrate that S1R protects HCC cells against sorafenib and subsequent ferroptosis. A better understanding of the role of S1R in ferroptosis may provide novel insight into this biological process.

Mechanisms of Ferroptosis and Relations With Regulated Cell Death: A Review.

Ferroptosis is a newly identified form of nonapoptotic regulated cell death (RCD) characterized by iron-dependent accumulation of lipid peroxides. It is morphologically and biochemically different from known types of cell death. Ferroptosis plays a vital role in the treatment of tumors, renal failure, and ischemia reperfusion injury (IRI). Inhibition of glutathione peroxidase 4 (GPX4), starvation of cysteine, and peroxidation of arachidonoyl (AA) trigger ferroptosis in the cells. Iron chelators, lipophilic antioxidants, and specific inhibitor prevent ferroptosis. Although massive researches have demonstrated the importance of ferroptosis in human, its mechanism is not really clear. In this review, we distanced ourselves from this confusion by dividing the mechanisms of ferroptosis into two aspects: processes that facilitate the formation of lipid peroxides and processes that suppress the reduction of lipid peroxides. At the same time, we summarize the relations between ferroptosis and several types of cell death.