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Cold Spring Harbor Asia (CSHA) conference on ferroptosis

In our current work, we identify and validate the first multi-species inhibitor of ferroptosis suppressor protein-1 (FSP1), called viFSP1 (versatile inhibitor of FSP1). FSP1, along with extra-mitochondrial ubiquinone (CoQ10) or vitamin K, represents one of the key ferroptosis surveillance system in mammals. Since standard therapy-resistant and metastasizing cancers show high vulnerability to ferroptosis, targeting FSP1 might attenuate tumor growth in certain tumor contexts. Moreover, a better understanding of the molecular mechanisms of FSP1 in ferroptosis prevention is of utmost importance for the rationale design of FSP1-based therapies. Using a combination of computational predictions and random mutagenesis approaches, we now unravel not only the mechanism-of-action of viFSP1 and iFSP1, another inhibitor specific for the human enzyme published earlier by us (Doll et al., Nature 2019), but also the enzymatic mechanism of how FSP1 reduces its main substrates CoQ10 and vitamin K, thereby protecting against lipid peroxidation and ferroptosis (Figure taken and modified from Nakamura et al., Nat Struct Mol Biol 2023)(see also “A Rising Star: Inducing Ferroptosis with Innovative Compounds for Cancer Therapy“).

Delighted to be listed as one of the Highly Cited Researchers again this year. This success is thanks to the tremendous efforts of an outstanding team and fantastic collaborators that I have had the pleasure of working with over the past few years! Clarivate unveiled the 2023 Highly Cited Researchers™ list with 6,849 Highly Cited Researchers in 2023, coming from more than 1,300 institutions in 67 nations and regions. Germany with 336 researchers is ranked fourth after United States, China and United Kingdom.

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In this comprehensive review article, we provide an up-to-date overview of the multiple roles that iron plays in a variety of cellular and metabolic processes. We highlight how cells handle and transport iron within cells and between organs, and how they use it in the biosynthetic pathways of haem and iron-sulphur cluster-containing proteins. We also discuss the regulatory mechanisms of how cells store and mobilise iron from professional iron storage or release proteins, and the so-called labile iron pool. We emphasise the importance of balanced cellular and tissue iron levels, as disturbances of these are ultimately associated with the development of disease and susceptibility to ferroptosis, a non-apoptotic form of cell death characterised by iron-dependent lipid peroxidation. We believe that a better understanding of the underlying regulatory nodes of iron metabolism is essential for the rational development of new therapeutic options to combat iron-related diseases (Figure adopted from Galy et al., Nat Rev Mol Cell Biol 2023).

Galy, B. et al. (2023) Mechanisms controlling cellular and systemic iron homeostasis. Nature Reviews Molecular Cell Biology

In our recent work, we demonstrate that brequinar (BQR), an established and potent inhibitor of dihydroorotate dehydrogenase (DHODH), sensitizes to ferroptosis via ferroptosis suppressor protein-1 (FSP1) and not via DHODH as previously suggested by Mao et al. (2021). The reason Mao et al. concluded that mitochondrially localised DHODH could be a therapeutic vulnerability in cancer was because of the extremely high concentrations of BQR used throughout, but which also inhibit FSP1, as shown in our recent study. Furthermore, we provide conclusive evidence that it is the short form (alias “cytosolic” or “somatic” form”) of glutathione peroxidase 4 (GPX4) that effectively protects cells from ferroptosis. Our results therefore suggest that DHODH plays only a minor role, if any, in ferroptosis surveillance, while GPX4 and FSP1 remain the major systems for suppressing ferroptosis in mammalian cells. Our study should, however, not discourage ongoing efforts to study DHODH as a valid anticancer target due to its role well-established role in pyrimidine synthesis and hence cell proliferation (Figure taken from Mishima et al., Nature 2023).

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In this study, we introduce the small molecule compound class of 3-phenylquinazolinones, termed icFSP1, as the first in vivo active ferroptosis suppressor protein-1 (FSP1)-specific inhibitors. Unlike the first described FSP1 inhibitor iFSP1 (Doll et al., Nature 2019), icFSP1 induces subcellular relocalisation of FSP1 from membranes and phase separation prior to lipid peroxidation and ferroptosis. (Liquid-liquid) phase separation is a physicochemical process similar to the separation of water and oil and is involved in many cellular processes, including cell signalling and transcriptional regulation. In addition, phase separation has also been linked to various pathologies such as neurodegeneration and cancer. We further show that icFSP1-induced phase separation of FSP1 requires different structural elements in FSP1 and that pharmacological treatment of tumour-bearing mice impairs tumour growth. Our results therefore establish a link between the process of phase separation and ferroptosis and should spur future efforts to develop in vivo applicable drugs for the treatment of certain cancers considered to be vulnerable to ferroptosis (Figure taken and modified from Nakamura et al., Nature 2023).

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In this perspective article, we provide an overview of the diverse functions of vitamin K (K comes from Koagulation, the German word for coagulation) in physiology and metabolism including blood clotting and bone metabolism. As an essential cofactor of γ-carboxyglutamyl carboxylase in the canonical vitamin K cycle, vitamin K has also vitamin K-independent functions, such as regulation of gene expression. In addition, vitamin K has recently been shown to also act as a potent “anti-ferroptotic” molecule by preventing lipid peroxidation of cell membranes in cultured cells and mice (see Mishima et al., Nature 2022). This non-canonical anti-ferroptotic function, which requires regeneration of oxidized vitamin K by ferroptosis suppressor protein-1 (FSP1) and NAD(P)H, has been termed the “Mishima cycle” to clearly distinguish this function from the canonical function in blood coagulation. Future studies will shed light on whether vitamin K together with FSP1 has similar or even additional functions in organisms that are also highly dependent on vitamin K, such as plants and bacteria (Figure taken from Mishima et al., Nat Metab 2023).

Mishima, E. et al. (2023) Diverse biological functions of vitamin K: from coagulation to ferroptosis. Nature Metabolism

The first EMBO Workshop entitled “FERROPTOSIS: When metabolism meets cell death” organized by Drs. Marcus Conrad (Helmholtz Munich, DE), José Pedro Friedmann Angeli (University of Würzburg, DE), Maria Fedorova (Technical University of Dresden, DE) and Xuejun Jiang (Memorial Sloan-Kettering Cancer Center, US) took place from April 23 – 27, 2023 in Kloster Seeon, Germany, close to Lake Chiemsee and the Bavarian Alps. We had an excellent lineup of speakers, a huge number of outstanding posters and intense and fruitful discussions. There was clear consensus among the participants that this was a truly exciting and stimulating workshop, sparking new ideas and collaborations.

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FERROPTOSIS: When metabolism meets cell death

The Deutsche Forschungsgemeinschaft (DFG) has appointed Marcus Conrad as a new member of the DFG’s Hinterzarten Circle on Cancer Research. The Hinterzarten Circle is a roundtable which serves as a regular discussion forum. Membership consists of medical and biological scientists working in the field of cancer research. The annual meeting discusses novel findings in the field of cancer-related basic research and the diagnosis and therapy of malignant tumours. This annual roundtable, held in relative seclusion, aims to encourage intensive discussion between scientists from various disciplines engaged in basic research and those conducting clinical research. The five members of the Hinterzarten Circle are appointed by the DFG for five years.

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Very honored to see that our work has been recognized again by the broader scientific community. Each year, Clarivate™ identifies the world’s most influential researchers ─ the select few who have been most frequently cited by their peers over the last decade. In 2022, fewer than 7,000, or about 0.1%, of the world’s researchers, in 21 research fields and across multiple fields, have earned this exclusive distinction. Marcus Conrad is among this elite group recognized for your exceptional research influence, demonstrated by the production of multiple highly-cited papers that rank in the top 1% by citations for field and year in the Web of Science™.

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The Cold Spring Harbor Asia (CSHA) conference on “Iron, Reactive Oxygen Species & Ferroptosis in Life, Death & Disease” organized by Drs. Quan Chen (Nankai University, China), Marcus Conrad (Helmholtz Munich, Germany), Xuejun Jiang (Memorial Sloan-Kettering Cancer Center, USA), Hozumi Motohashi (Tohoku University, Japan), Brent Stockwell Columbias University, USA) and Shinya Toyokuni (Nagoya University, Japan) took place from October 10 – October 14, 2022, at Awaji Yumebutai Conference Center, JAPAN. Despite all the hurdles with the COVID pandemics, this second openly accessible conference on ferroptosis was a true success as new findings and developments in the field were intensely discussed among basic scientists, physicians and representatives from pharma/biotech industry.

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In this study, we show that vitamin K is a potent suppressor of ferroptosis by preventing oxidative damage to cellular membranes. So far, vitamin K has been well-known for its role in blood clotting and bone calcification. Its discovery dating almost 100 year ago was awarded with the Nobel Prize in Physiology or Medicine to Henrik Carl Peter Dam and Edward Adelbert Doisy in 1943. We further report that ferroptosis suppressor protein-1 (FSP1) reduces oxidized vitamin K to its hydroquinone form, thus driving a novel non-canonical vitamin K cycle that we tentatively name the “Mishima cycle”. Finally, we demonstrate that FSP1 is the long sought-after warfarin-resistant vitamin K reductase, thus solving one of the last riddles in vitamin K biology. Findings presented in our present work will therefore have immediate implications for both vitamin K and ferroptosis research (Figure adopted from Mishima et al., Nature 2022).

Mishima, E. et al. (2022). A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature

The newly launched consortium “FERROPath” involves six partners in Germany, located in Munich, Dresden, Regensburg and Essen, who aim to identify and validate common ferroptotic signatures and molecular mechanisms in organs mostly affected by ischemia/reperfusion injury (IRI), such as brain, liver, lung and kidney. IRI occurs when the blood flow to a certain organ is transiently interrupted causing additional damage to the affected tissue due to the generation of high levels of oxygen radicals including lipid peroxidation. IRI is therefore a serious complication, responsible for a variety of clinically important conditions including stroke, acute kidney injury and organ transplantation. As such, understanding the molecular mechanisms and elucidating common molecular signatures of ferroptosis will be of utmost importance for the development of novel therapies based on next generation ferroptosis inhibitors.

Delighted to announce that our research of the last years has again been widely appreciated by the broader scientific community, demonstrated by multiple highly-cited papers that rank in the top 1% by citations for field and year in the Web of Science™. Each year, Clarivate™ identifies the world’s most influential researchers ─ the select few who have been most frequently cited by their peers over the last decade. In 2021, 6,602 researchers from more than 70 countries and regions have earned this exclusive distinction (Germany ranks five with 331 scientists).

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On October 01, we have officially started our DFG (Deutsche Forschungsgemeinschaft) funded Priority Programme “Ferroptosis: from Molecular Basics to Clinical Applications” (SPP 2306) which will fund 25 projects scattered all over Germany for up to six years. The overall goal of the program is to better understand the molecular mechanisms of ferroptosis as the basis for the development of novel therapies based on ferroptosis modulation.

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Here, we highlight the role of lipid metabolizing enzymes, distinct (phospho)lipid species and their oxidative modification as well as relevant metabolic pathways in the context of sensitization of cells toward ferroptosis. We further discuss outstanding questions how lipid peroxidation and related secondary products may contribute to the rupturing of cellular membranes, the final step in ferroptosis execution (Cover art from Trends in Endocrinology & Metabolism. July 2021).