Ferroptosis: a novel cell death form will be a promising therapy target for diseases

Recently, Friedmann Angeli et al. [1] reported that the loss of ferroptosis regulation enzyme glutathione peroxidase 4 (GPX4)will cause an overwhelming ferroptosis of renal cells, which eventually induces renal failure. Yet, liproxstatin-1, a novel potent ferroptosis inhibitor, is able to alleviate tissue injury of ischemia/reperfusion-induced renal injury. This study smartly expanded the research on nonapoptotic cell death, ferroptosis, as researchers were just focused on its effect on tumor and neuronal diseases before [2,3]. Actually, ferroptosis is related to multiple pathophysiological processes, and triggering or inhibiting ferroptosis will be novel therapy strategies for many diseases, such as atherosclerosis, angiocardiopathy, and diabetes. In their research, the complex lipid oxidation was also investigated, which provided new possibilities for redox-target therapy [1]. Apoptosis has been considered as the major form of cell death, but sometimes target apoptosis cannot achieve satisfactory therapeutic effect on tumor and other diseases [4]. Consequently, nonapoptotic cell death processes have continuously been explored and discussed, including necroptosis and ferroptosis. In 2012, Dixon et al. [5] found for the first time that the oncogenic RAS-selective lethal compounds can trigger a unique iron-dependent form of nonapoptotic cell death, ferroptosis which is a totally new pattern of cell death. It is different from apoptosis, autophagy, and necrosis in morphology (smaller mitochondrial with increased membrane density), biochemistry, and genetics. Furthermore, it is specifically associated with iron and characterized by distinctive lipid oxidation, and expands the study on the network of nonapoptotic cell death. With further research on ferroptosis, the occurrence and regulation mechanism of ferroptosis has gradually been revealed (Fig. 1) [1, 5–9]. Factors involved in the iron metabolism regulation system, such as transferrin (TF)-receptor (TFR) and divalent metal transporter 1, are activated to induce iron accumulation, and then fenton reaction is evoked during ferroptosis. Heat shock protein beta-1 (HSPB1) was found to be a negative ferroptosis regulator which can reduce iron accumulation in cancer cells [6]. Although Dixon et al. [5] have demonstrated that NADPH oxidases provide one source of reactive oxygen species (ROS) during ferroptosis, the general ROS production pathway is still unknown, because it is independent of the major ROS generator, the mitochondrial electron transport chain. The cystine/glutamate transporter system xc − plays an important role in maintaining cellular glutathione (GSH) and redox equilibrium, and some ferroptosis inducers were found to promote ROS production by depressing system xc − or restricting the anti-oxidant effect of GPX4, an enzyme that is inactivated by GSH depletion [7]. In addition, p53 inhibits cystine uptake and promotes ROS-induced stress by repressing the key system xc – component, SLC7A11, suggesting a novel anti-cancer mechanism of this tumor suppressor gene [8]. Sorafenib, a multikinase inhibitor and effective anti-tumor drug, was found to have cytotoxic effects on the hepatocellular carcinoma (HCC) cells through triggering the iron-dependent oxidative cell death, ferroptosis. And this form of cell death is enhanced in retinoblastoma (Rb) proteinnegative HCC cells [9]. Thus, blocking the activities of antioxidase, system xc –, GSH synthetise, and GPX4, or increasing the concentration of iron would induce extremely aberrant ROS production and lipid peroxidation, the high-risk factors for inducing ferroptosis [1]. Accordingly, a series of ferroptosis inducers and inhibitors have been developed and tested (Table 1) [1,5,10–12]. These are useful tools for further study of the specific mechanism and process of ferroptosis. Considering that the change of mitochondria was the major morphology difference in those multiple types of cell death and that GPX4, an essential ferroptosis regulator gene with the six mitochondria genes exhibiting abnormal expression during ferroptosis [5], locates in mitochondrion [7], we believe that mitochondria may play a central role in ferroptosis. Some researchers have showed that mitochondrial oxidation is not the lethal factor for ferroptosis, and the outer mitochondrial membrane rupture just represents the irreversible ferroptosis [1,5]. How does the contradiction emerge? The crucial target for oxidation is still unknown at present. Besides mitochondria, other sites of ROS production and accumulation may also be important for ferroptosis. During ferroptosis, the endoplasmic reticulum (ER) and attached ribosome may be the first damaged sites which then transmit the damage signal to the mitochondria. Just as in photodynamic stress therapy, the initial ROS stimulate reticulophagy by impairing ER, and this oxidative damage is rapidly conveyed to the mitochondria and causes cell death [13]. ROS, as important signaling molecules, are involved in multiple pathologic processes, such as autophagy. Whether the compensatory action autophagy can be arisen to remove ferroptosis injured cells? How does this cross-talk occur? These are important questions to be answered in the future. Acta Biochim Biophys Sin, 2015, 47(10), 857–859 doi: 10.1093/abbs/gmv086 Advance Access Publication Date: 7 September 2015 Research Highlight