Ferroptosis and Brain Injury

Abstract

Ferroptosis is a nonapoptotic form of cell death characterized by the iron-dependent accumulation of toxic lipid reactive oxygen species. Small-molecule screening and subsequent optimization have yielded potent and specific activators and inhibitors of this process. These compounds have been employed to dissect the lethal mechanism and implicate this process in pathological cell death events observed in many tissues, including the brain. Indeed, ferroptosis is emerging as an important mechanism of cell death during stroke, intracerebral hemorrhage, and other acute brain injuries, and may also play a role in certain degenerative brain disorders. Outstanding issues include the practical need to identify molecular markers of ferroptosis that can be used to detect and study this process in vivo, and the more basic problem of understanding the relationship between ferroptosis and other forms of cell death that can be triggered in the brain during injury.

Keywords: GPX4; Glutathione; Iron; Ischemia-repurfusion injury; Necrosis; PUFAs; Polyunsaturated fatty acids; Stroke.

Fig. 1.

(a) Key metabolites and enzymes (bold text) involved in the ferroptosis pathway. Insets highlight the regulation of cystine import by glutamate levels (upper) and provide additional detail on the regulation of lipid metabolism in ferroptosis (lower). The purple shaded box highlights the iron-catalyzed, free radical-mediated chain reaction of lipid oxidation. (b) Table listing key small molecule modulators of ferroptosis and associated mechanisms of action.