The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of non-apoptotic cell death termed ferroptosis. Ferroptotic death is morphologically, biochemically and genetically distinct from apoptosis, various forms of necrosis, and autophagy. This process is characterized by the overwhelming, iron-dependent accumulation of lethal lipid ROS. Unlike other forms of apoptotic and non-apoptotic death, this requirement for ROS accumulation appears to be universal.
The specific role of iron in ferroptosis is yet unclear. Ferroptosis cannot be explained by a simple increase in H₂O₂-dependent, iron-catalyzed ROS production (i.e. Fenton chemistry), as H₂O₂-induced death is distinct from RSL-induced ferroptosis[1]. Glutathione (GSH) peroxidase 4 (GPX4) is a crucial inhibitor of ferroptosis, and its activity relies on GSH levels. Despite a clear mechanistic overlap between oxytosis and ferroptosis, including the dependence on inhibition of the system X_c⁻ Cys/Glu antiporter, a decrease in GSH levels and the presence of lipid peroxidation, ferroptosis seems to depend mainly on iron instead of calcium signaling[2].

KEYWORDS: Ferroptosis | inhibitor | supplier | oncogenic |RAS| lethal | erastiniron-dependent | non-apoptotic | apoptosis | necrosis | autophagy | accumulation | lipidROS| Glutathione |GSH| peroxidase 4 |GPX4