Perspective article in Nature Chemical Biology
In this Perspective article, we discuss the chemistry of lipid peroxidation, the oxidative modification of lipid bilayers and hallmark of ferroptosis, and how it can be triggered by enzymatic and more importantly by non-enzymatic routes in cells. Ferroptosis is emerging as one of the key cell death pathways contributing to the initial loss of cells and to organ failure in numerous degenerative diseases. On the contrary, activating this form of cell death holds the great potential to fight difficult to treat cancers. Therefore, an in-depth understanding of the molecular underpinnings of lipid peroxidation is mandatory as it offers exciting and still largely untapped opportunities for novel pharmacological interventions.
Article published in Nature
In this article, we introduce the second ferroptosis preventing system, called ferroptosis suppressor protein-1 (FSP1), that acts independently of the canonical cysteine/glutathione/glutathione peroxidase 4 (GPX4) axis. Unlike GPX4 that protects against detrimental lipid peroxidation by reducing hydroperoxides in lipid bilayers to their corresponding alcohols in a glutathione dependent manner, FSP1 regenerates extramitochondrial ubiquinone that prevents lipid autoxidation by reducing lipid radical species. Since FSP1 is expressed in most cancer cell lines, it represents an attractive drug target for anticancer strategies (Figure adopted from Doll et al., Nature 2019).
Perspective article in Nature Reviews Cancer
In this Perspective article we summarize the known mechanisms that regulate sensitivity to ferroptosis in cancer cells and how the modulation of metabolic pathways regulating ferroptosis sensitivity might reshape the tumor niche, leading to an immunosuppressive microenvironment that ultimately promotes tumor growth and progression. We further discuss how this metabolic rewiring particularly during dedifferentiation of certain cancer cells leaves a vulnerability towards ferroptosis, which, in turn, may offer unprecedented pharmacological opportunities to eradicate difficult to treat cancers (Figure adopted from Friedmann Angeli et al., Nat Rev Cancer 2019).
First conference on “ferroptosis” open to the public
The Cold Spring Harbor Asia (CSHA) conference on “Iron, Reactive Oxygen Species & Ferroptosis in Life, Death & Disease” organized by Drs. Quan Chen, Institute of Zoology, CAS, CHINA, Marcus Conrad, Helmholtz Zentrum München, GERMANY, Xuejun Jiang, Memorial Sloan-Kettering Cancer Center, USA, and Brent Stockwell, HHMI/Columbia University, USA, took place in Suzhou, China, from November 26-30, 2018 (https://www.csh-asia.org/2018meetings/ros.html). With more than 200 participants it was a great success as it also brought together many scientists who have made landmark contributions to this emerging and exciting field. It was thus decided to organize a follow-up conference to be announced soon.
Review article in Genes & Development
In our most recent review article we outline the potential similarities and differences concerning the role of lipid peroxidation and associated ferroptosis in different species ranging from mammals, non-mammalian vertebrates, plants, fungi to bacteria (Figure adopted from Conrad et al., Genes Dev 2018).
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