Article published in Cell
Exactly 200 years ago, the Swedish scientist Jöns Jacob Berzelius discovered the trace element selenium, who named it after the Greek goddess of the moon Selene. The ferroptosis regulator GPX4 is one of distinct 25 selenoproteins in man with selenium in form of selenocysteine in its active site. In our present work published in Cell we now show that selenium utilization of GPX4 provides full resistance to peroxide-mediated enzyme inactivation and associated ferroptotic cell death. As mammals and other vertebrates express selenium-containing GPX4, the exploitation of a rich set of polyunsaturated fatty acids incorporated in membranes (which are inherently prone to oxidative damage) afforded the development of complex brains (Graphical Abstract. Source: Ingold et al., Cell, 2018).
Primer article in Cell
A Primer article published in Cell provides a state-of-the-art review about the current understanding of the molecular underpinnings of ferroptotic cell death and its implication in physiological and pathophysiological contexts. It also advises on tools and guidelines for the study of this disease-relevant form of regulated cell death.
Review article in Trends in Pharmacological Sciences
In our most recent review article published in Trends in Pharmacological Sciences we provide a critical overview about what we know today about the molecular mechanisms of ferroptosis, its involvement in diverse (patho)physiological contexts and the development of inhibitors targeting the process of lipid peroxidation.
Mechanism-of-action of liproxstatin-1 unveiled
Along with Prof. Derek Pratt, University of Ottawa, we now provide evidence that the potent ferroptosis inhibitors ferrostatin-1 and liproxstatin-1 act as superior radical-trapping antioxidants in lipid bilayers rather than as lipoxygenase inhibitors. We had previously identified liproxstatin-1 as a highly specific, in vivo efficacious ferroptosis inhibitor, being active in in the low nanomolar range with good drug-like properties (see also Friedmann Angeli et al., Nat Cell Biol 2014). In tissues, liproxstatin-1 confers its anti-ferroptotic role by dampening detrimental lipid peroxidation (see also Kagan et al., Nat Chem Biol 2017).
Two articles on ferroptosis in
Nature Chemical Biology
In two publications published back-to-back in the journal Nature Chemical Biology we demonstrate that acyl-CoA synthetase long-chain family member 4 (ACSL4) is a key downstream player in ferroptotic cell death. The mechanism of ACSL4 in the ferroptotic process relies on its function to activate preferably long-chain polyunsaturated fatty acids (PUFA), which when esterified in lipid bilayers (i.e. phosphatidylethanolamines), contribute to the generation of proximate signals for the ferroptotic death program. Moreover, ACSL4 expression was shown to dictate sensitivity versus resistance towards ferroptosis in a subset of triple negative breast cancer cells, indicating that ACSL4 might be developed as a future stratification marker in patients suffering from certain cancers. Hence, our studies add ACSL4 as an essential component in ferroptosis.
Doll, S. et al. (2017): Acsl4 Dictates Ferroptosis Sensitivity by Shaping Cellular Lipid Composition. Nature Chemical Biology
Kagan, VE. et al. (2017): Oxidized Arachidonic and Adrenic PEs Navigate Cells to Ferroptosis. Nature Chemical Biology