Emerging aspects in the regulation of ferroptosis

Lipid peroxidation has been associated with a wide array of (patho)physiological conditions. Remarkably, in the last few years, a novel cell death modality termed ferroptosis was recognized as a process initiated by iron-dependent oxidation of lipids. The sensitivity to ferroptosis is determined by the activity of antioxidant systems working on the repair of oxidized phospholipids and also metabolic pathways controlling the availability of substrates susceptible to lipid peroxidation. Non-enzymatic antioxidants such as vitamin E, which has long been acknowledged as an efficient inhibitor of lipid peroxidation, play an important and often neglected role in subverting ferroptosis. Recent works dissecting the mechanisms that determine ferroptosis sensitivity have provided further insights into the contribution of alternative metabolic pathways able to suppress lipid peroxidation. Specifically, the role of ubiquinone and tetrahydrobiopterin (BH4) has been brought forth, with the identification of specific enzymatic systems responsible for their regeneration, as critical factors suppressing ferroptosis. Therefore, in the present manuscript, we address these emerging concepts and propose that the characterization of these antioxidant repair mechanisms will not only open a new understanding of disease conditions where ferroptosis plays a role but also offer opportunities to identify and sensitize cells to ferroptosis in the context of cancer treatment.