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Carsten Berndt, Hamed Alborzinia, Jan P. Böttcher, Simone Brabletz, Thomas Brabletz, Bernhard Brüne, Julia Esser-von Bieren, Maria Fedorova, José Pedro Friedmann Angeli, Manuel A. Friese, Dominic C. Fuhrmann, Ana J. García-Sáez,Magdalena Götz, Linda Hammerich, Aicha Jeridi, David B. Konrad, Andreas Linkermann, Tom Lüdde, Axel Methner, Martina Muckenthaler, Almut Schulze, Andreas Trumpp, Vivek Vikantaramani, Silvia von Karstedt, Frank Westermann, Marcus Conrad
Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells’ susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with – or caused by – ferroptosis.
Original publication:
Ferroptosis in Health and Disease
Carsten Berndt, Hamed Alborzinia, Vera Skafar Amen, Scott Aytone, Uladzimir Barayeu, Alexander Bartelt, Hülya Bayir, Christina M. Bebber, Kivanc Birsoym, Jan P. Böttcher, Simone Brabletz, Thomas Brabletz, Ashley R. Brown, Bernhard Brüne, Giorgia Bulli, Alix Bruneau, Quan Chent, Gina M. DeNicolau, Tobias P. Dick, Ayelén Distéfano, Scott Dixon, Jan Broder Engler, Julia Esser-von Bieren, Maria Fedorova, José Pedro Friedmann Angeli, Manuel A. Friese, Dominic C. Fuhrmann, Ana J. García-Sáez, Karolina Garbowicz, Magdalena Götz, Wei Guae, Linda Hammerich, Behrouz Hassannia, Xuejun Jiang, Aicha Jeridi, Jun Pyo Kang, Valerian E Kagan, David B. Konrad, Stefan Kotschi, Peng Lei, Marlene le-Tertre, Sima Lev, Deguang Liang, Andreas Linkermann, Carolin Lohr, Svenja Lorenz, Tom Lüdde, Axel Methner, Bernhard Michalkeau, Anna V. Milton, Junxia Min, Eikan Mishima, Sebastian Müller, Hozumi Motohashi, Martina Muckenthaler, Shohei Murakami, James A. Olzmann, Gabriela Pagnuss, Zijan Pan, Thales Papagiannakopoulos, Lohans Pedrera Puentes, Derek A. Pratt, Bettina Proneth, Lukas Ramsauer, Raphael Rodriguez, Yoshiro Saito, Felix Schmidt, Carina Schmitt, Almut Schulze, Annemarie Schwab, Anna Schwantes, Mariluz Soul, Benedikt Spitzlberger, Brent R. Stockwell, Leonie Thewes, Oliver Thorn-Seshold, Shinya Toyokuni, Wulf Tonnus, Andreas Trumpp, Peter Vandenabeele, Tom Vanden Berghe, Vivek Vikantaramani, Felix C. E. Vogel, Silvia von Karstedt, Fudi Wang, Frank Westermann, Michele Wölk, Katherine Wu, Xin Yang, Fan Yu, Yilong Zou, and Marcus Conrad
Redox Biology May 24; in press
Our most recent collaborative Nature publication with following partners from the SPP 2306:
Conrad M & Böttcher JP
Expansion of antigen-experienced CD8+ T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer1. Interleukin-2 (IL-2) acts as a key regulator of CD8+ cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability2,3. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE2), a known negative regulator of immune response in the tumour microenvironment4,5, is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8+ TILs via the PGE2 receptors EP2 and EP4. Mechanistically, PGE2 inhibits IL-2 sensing in TILs by downregulating the IL-2Rγc chain, resulting in defective assembly of IL-2Rβ-IL2Rγc membrane dimers. This results in impaired IL-2-mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE2 signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE2 in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential.
Please find more information here:
Original publication:
PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function.
Morotti M, Grimm AJ, Hope HC, Arnaud M, Desbuisson M, Rayroux N, Barras D, Masid M, Murgues B, Chap BS, Ongaro M, Rota IA, Ronet C, Minasyan A, Chiffelle J, Lacher SB, Bobisse S, Murgues C, Ghisoni E, Ouchen K, Bou Mjahed R, Benedetti F, Abdellaoui N, Turrini R, Gannon PO, Zaman K, Mathevet P, Lelievre L, Crespo I, Conrad M, Verdeil G, Kandalaft LE, Dagher J, Corria-Osorio J, Doucey MA, Ho PC, Harari A, Vannini N, Böttcher JP, Dangaj Laniti D, Coukos G.
Nature. 2024 May;629(8011):426-434. doi: 10.1038/s41586-024-07352-w. Epub 2024 Apr 24. PMID: 38658764 Free PMC article.
SPP 2306 Start-up funding: Markers of lipid peroxidation and ferroptosis sensitivity in metastasis to liver and lung
Dr. Christina Bebber,
CECAD, Cluster of Excellence for Aging Research, University of Cologne
Dr. Felix C. E. Vogel,
Division of Tumour Metabolism and Microenvironment, German Cancer Research Center (DKFZ), Heidelberg
Melanoma is a highly aggressive skin cancer that arises from the melanocytic lineage. Several driver-gene mutations are associated with tumor progression; some have already been used for targeted therapies. Despite the recent advances and effectiveness of such targeted therapies, subpopulations of melanoma cells can inevitably acquire resistance, which ultimately challenges anti-tumor responses to subsequent anticancer drugs. This joint grant application aims to uncover the mechanism of resistance to drug treatment in melanoma, which will be the basis of developing innovative combinatorial strategies to combat melanoma by induction of ferroptosis.
An collaborative Nature publication with several partners from the SPP 2306:
Konrad DB, Garcia-Saez A, Fedorova M, Trumpp A, Conrad M, Friedmann Angeli JP
Ferroptosis is a form of cell death that has received considerable attention not only as a means to eradicate defined tumour entities but also because it provides unforeseen insights into the metabolic adaptation that tumours exploit to counteract phospholipid oxidation1,2. Here, we identify proferroptotic activity of 7-dehydrocholesterol reductase (DHCR7) and an unexpected prosurvival function of its substrate, 7-dehydrocholesterol (7-DHC). Although previous studies suggested that high concentrations of 7-DHC are cytotoxic to developing neurons by favouring lipid peroxidation3, we now show that 7-DHC accumulation confers a robust prosurvival function in cancer cells. Because of its far superior reactivity towards peroxyl radicals, 7-DHC effectively shields (phospho)lipids from autoxidation and subsequent fragmentation. We provide validation in neuroblastoma and Burkitt’s lymphoma xenografts where we demonstrate that the accumulation of 7-DHC is capable of inducing a shift towards a ferroptosis-resistant state in these tumours ultimately resulting in a more aggressive phenotype. Conclusively, our findings provide compelling evidence of a yet-unrecognized antiferroptotic activity of 7-DHC as a cell-intrinsic mechanism that could be exploited by cancer cells to escape ferroptosis.
SPP 2306 Start-up funding: Deciphering the role of hepcidin in ferroptotic-mediated liver damage in hemochromatosis
Dr. Carolin Lohr,
Division for Gastroenterology, Hepatology and Infectiology, University Hospital Duesseldorf
Dr. Marlene le Tertre,
Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg
Ferroptosis has recently been linked to the iron-mediated liver damage observed in hemochromatosis patients. This inherited iron overload disorder is due either to a defect in hepcidin expression (a small peptide that down-regulates the iron exporter ferroportin) or to a resistance of ferroportin to hepcidin. Interestingly, hemochromatosis patients with an hepcidin deficiency develop more severe liver damage. We suggest that the presence of hepcidin, acting beyond its iron-regulatory function, influences ferroptosis-mediated organ damage in haemochromatosis. To investigate this question, we will notably compare the effects of induced ferroptosis-mediated liver disease in two hemochromatosis mouse models that differ in hepcidin expression.
ERC Consolidator Grant for José Pedro Friedmann Angeli
One of our SPP 2306 steering committee members – José Pedro Friedmann Angeli – has been awarded a European research prize. With his work, the Würzburg professor wants to contribute to innovative therapies against cancer.
ERC Consolidator Grant: DeciFERR
Deciphering and exploiting ferroptosis regulatory mechanism in cancer
Please find more information here:
Nat Rev Mol Cell Biol.: Mechanism controlling cellular and systemic iron homeostasis.
Our most recent collaborative review with several partners from the SPP 2306: Galy B, Conrad M, Muckenthaler M.
Mechanisms controlling cellular and systemic iron homeostasis.
Nat Rev Mol Cell Biol. 2023 Oct 2. doi: 10.1038/s41580-023-00648-1. Online ahead of print. PMID: 37783783 Review.
Highly orchestrated regulatory systems control cellular and systemic iron fluxes ensuring sufficient iron delivery to target proteins is maintained, while limiting its potentially deleterious effects in iron-mediated oxidative cell damage and ferroptosis.
In this Review, we discuss how cells acquire, traffick and export iron and how stored iron is mobilized for iron-sulfur cluster and haem biogenesis. Furthermore, we describe how these cellular processes are fine-tuned by the combination of various sensory and regulatory systems, such as the iron-regulatory protein (IRP)-iron-responsive element (IRE) network, the nuclear receptor co-activator 4 (NCOA4)-mediated ferritinophagy pathway, the prolyl hydroxylase domain (PHD)-hypoxia-inducible factor (HIF) axis or the nuclear factor erythroid 2-related factor 2 (NRF2) regulatory hub. We further describe how these pathways interact with systemic iron homeostasis control through the hepcidin-ferroportin axis to ensure appropriate iron fluxes. This knowledge is key for the identification of novel therapeutic opportunities to prevent diseases of cellular and/or systemic iron mismanagement.
DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition.
Our most recent Nature article:
Mishima E, Nakamura T, Zheng J, Zhang W, Mourão ASD, Sennhenn P, Conrad M.
Original publication:
DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition.
Mishima E, Nakamura T, Zheng J, Zhang W, Mourão ASD, Sennhenn P, Conrad M.
Nature. 2023 Jul;619(7968):E9-E18. doi: 10.1038/s41586-023-06269-0. Epub 2023 Jul 5.PMID: 37407687 No abstract available.
A previous report suggested that dihydroorotate dehydrogenase (DHODH) protects against mitochondrial damage and ferroptosis and therefore may present a targetable vulnerability in cancer (Mao et al. Nature 2021). Since these conclusions were mainly based on exceedingly high concentrations of the DHODH inhibitor brequinar (BQR) used throughout this study, we questioned these conclusions and now demonstrate that high concentrations of BQR (and other DHODH inhibitors) sensitize to ferroptosis via inhibition of ferroptosis suppressor protein-1 (FSP1) and not via DHODH. We further show that it is the short form of glutathione peroxidase 4 (GPX4) (and not the mitochondrial form) that is key in protecting against lipid peroxidation and ferroptosis. Our current study therefore reinforces the notion that properly controlled inhibitor concentrations are key before strong conclusions can be drawn (Mishima*, Nakamura*, Zheng* et al., Nature 2023)
see also:
Potentiating Cancer Vulnerability to Ferroptosis: Off-Targeting Effects of DHODH Inhibitors
LRP8-mediated selenocysteine uptake is a targetable vulnerability in MYCN-amplified neuroblastoma
Our most recent collaborative study with several partners from the SPP 2306
Conrad M, Schulze A, Trumpp A, Friedmann Angeli JP
Schematic representation for the proposed model of LRP8 inhibition essentiality. Comparison of selenium /selenocysteine uptake mechanisms via LRP8 and system Xc in proliferating MYCN- amplified cells, depicting the contribution of primarily LRP8/SELENOP supporting selenoprotein translation (left panel). Inhibition of LRP8 in system Xc low cell selectively triggers ferroptosis in MYCN-amplified neuroblastoma (right panel). SELENOP, Selenoprotein P; iSe, inorganic selenium; SeCys, Selenocysteine.
(Figure adopted from Alborzinia H et al., 2023 PMID: 37435859).
Ferroptosis has emerged as an attractive strategy in cancer therapy. Understanding the operational networks regulating ferroptosis may unravel vulnerabilities that could be harnessed for therapeutic benefit. Using CRISPR-activation screens in ferroptosis hypersensitive cells, we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN-amplified neuroblastoma cells from ferroptosis. Genetic deletion of LRP8 leads to ferroptosis as a result of an insufficient supply of selenocysteine, which is required for the translation of the antiferroptotic selenoprotein GPX4. This dependency is caused by low expression of alternative selenium uptake pathways such as system Xc– . The identification of LRP8 as a specific vulnerability of MYCN-amplified neuroblastoma cells was confirmed in constitutive and inducible LRP8 knockout orthotopic xenografts. These findings disclose a yet-unaccounted mechanism of selective ferroptosis induction that might be explored as a therapeutic strategy for high-risk neuroblastoma and potentially other MYCN-amplified entities.
Original publication:
LRP8-mediated selenocysteine uptake is a targetable vulnerability in MYCN-amplified neuroblastoma.
Alborzinia H, Chen Z, Yildiz U, Freitas FP, Vogel FCE, Varga JP, Batani J, Bartenhagen C, Schmitz W, Büchel G, Michalke B, Zheng J, Meierjohann S, Girardi E, Espinet E, Flórez AF, Dos Santos AF, Aroua N, Cheytan T, Haenlin J, Schlicker L, Xavier da Silva TN, Przybylla A, Zeisberger P, Superti-Furga G, Eilers M, Conrad M, Fabiano M, Schweizer U, Fischer M, Schulze A, Trumpp A, Friedmann Angeli JP.
EMBO Mol Med. 2023 Jul 12:e18014. doi: 10.15252/emmm.202318014. Online ahead of print. PMID: 37435859 Free article.
Nature. 2023 Jul
Original publication:
Phase separation of FSP1 promotes ferroptosis.
Nature. 2023 Jul;619(7969):371-377. doi: 10.1038/s41586-023-06255-6. Epub 2023 Jun 28. PMID: 37380771 Free PMC article.
Targeting ferroptosis has emerged as a therapeutic vulnerability in combating therapy-resistant and dedifferentiating cancers. Therefore, new in vivo active ferroptosis-inducing compounds are urgently needed. Here we introduce a novel compound class of ferroptosis inducing agents, called icFSP1, which targets ferroptosis suppressor protein-1 (FSP1), one of the guardians of ferroptosis. Unlike our first reported FSP1-specific inhibitor iFSP1 (Doll et al., Nature 2019), icFSP does not inhibit FSP1 directly, but causes membrane detachment and phase separation of FSP1. Phase separation is a physicochemical process that is involved in numerous cellular processes including cell signaling and transcriptional regulation and is known to play a role in neurodegenerative disease and cancer. We further demonstrate that icFSP1 impairs tumor growth in vivo by inducing phase separation of FSP1. Our study thus provides the basis for targeting FSP1 as a future approach to treat certain cancers by triggering ferroptosis.
see also:
New Approach in Cancer Therapy With Innovative Mechanism-of-Action for Ferroptosis Induction
MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis.
A collaborative study with two partners of the SPP 2306: Trumpp A, Westermann, F
Regulation of pro- and anti-ferroptotic players by oncogenic MYCN in MYCN-amplified neuroblastoma cells that may trigger ferroptosis when both cysteine and GSH availability is limited. Therapeutic intervention points are indicated in green.
(Figure adopted from Alborzinia H et al., 2022
PMID:35484422 ).
Aberrant expression of MYC transcription factor family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYCN induces massive lipid peroxidation on depletion of cysteine, the rate-limiting amino acid for glutathione (GSH) biosynthesis, and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death. The high cysteine demand of MYCN-amplified childhood neuroblastoma is met by uptake and transsulfuration. When uptake is limited, cysteine usage for protein synthesis is maintained at the expense of GSH triggering ferroptosis and potentially contributing to spontaneous tumor regression in low-risk neuroblastomas. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN-amplified neuroblastoma model. These findings provide a proof of concept of combining multiple ferroptosis targets as a promising therapeutic strategy for aggressive MYCN-amplified tumors.
Original publication:
MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis.
Alborzinia H, Flórez AF, Kreth S, Brückner LM, Yildiz U, Gartlgruber M, Odoni DI, Poschet G, Garbowicz K, Shao C, Klein C, Meier J, Zeisberger P, Nadler-Holly M, Ziehm M, Paul F, Burhenne J, Bell E, Shaikhkarami M, Würth R, Stainczyk SA, Wecht EM, Kreth J, Büttner M, Ishaque N, Schlesner M, Nicke B, Stresemann C, Llamazares-Prada M, Reiling JH, Fischer M, Amit I, Selbach M, Herrmann C, Wölfl S, Henrich KO, Höfer T, Trumpp A, Westermann F.
Nat Cancer. 2022 Apr;3(4):471-485. doi: 10.1038/s43018-022-00355-4. Epub 2022 Apr 28. PMID: 35484422 Free PMC article.
Hydropersulfides inhibit lipid peroxidation and ferroptosis by scavenging radicals
A collaborative study with several partners from the SPP 2306
(Dick TP, Friedmann Angeli JP, Schulze A):
Figure from Barayeu, U. et al., 2023
PMID: 36109647
Ferroptosis is a type of cell death caused by radical-driven lipid peroxidation, leading to membrane damage and rupture. Here we show that enzymatically produced sulfane sulfur (S0) species, specifically hydropersulfides, scavenge endogenously generated free radicals and, thereby, suppress lipid peroxidation and ferroptosis. By providing sulfur for S0 biosynthesis, cysteine can support ferroptosis resistance independently of the canonical GPX4 pathway. Our results further suggest that hydropersulfides terminate radical chain reactions through the formation and self-recombination of perthiyl radicals. The autocatalytic regeneration of hydropersulfides may explain why low micromolar concentrations of persulfides suffice to produce potent cytoprotective effects on a background of millimolar concentrations of glutathione. We propose that increased S0 biosynthesis is an adaptive cellular response to radical-driven lipid peroxidation, potentially representing a primordial radical protection system.
Original publication:
Hydropersulfides inhibit lipid peroxidation and ferroptosis by scavenging radicals.
Barayeu U, Schilling D, Eid M, Xavier da Silva TN, Schlicker L, Mitreska N, Zapp C, Gräter F, Miller AK, Kappl R, Schulze A, Friedmann Angeli JP, Dick TP. Nat Chem Biol. 2023 Jan;19(1):28-37. doi: 10.1038/s41589-022-01145-w. Epub 2022 Sep 15. PMID: 36109647 Free PMC article.
Mitochondrial ferritin expression in human macrophages is facilitated by thrombin-mediated cleavage under hypoxia
Dominik C. Fuhrmann, Sabrina Becker, and Bernhard Brüne
FEBS Lett. 2022 Nov 23. doi: 10.1002/1873-3468.
PMID: 36416578.
Ferritins are iron storage proteins, which maintain cellular iron homeostasis. Among these proteins, the ferritin heavy chain is well characterized, but the regulatory principles of mitochondrial ferritin (FTMT) remain elusive. FTMT appears to be cleaved from a 27 kDa to a 22 kDa form. In human macrophages, FTMT increased under hypoxia in a hypoxia-inducible factor 2-dependent manner. Occurrence of FTMT resulted from cleavage by thrombin, which was supplied by serum. Inhibition of thrombin as well as serum removal decreased FTMT, while supplementation of thrombin under serum-deprived conditions restored its expression. Besides hypoxia, thrombin facilitated FTMT expression after treatment with the ferroptosis inducer RSL3 and the pro-inflammatory stimulus lipopolysaccharide. This study provides insights into the regulation of FTMT under hypoxia and identifies thrombin as a FTMT maturation-associated peptidase.
Nature: A non-canonical vitamin K cycle prevents ferroptosis
Mishima, E. et al. (2022). Nature
In our most recent collaborative study with several partners from the SPP 2306 (Conrad, Fedorova, Linkermann), we report 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, and 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. Mechanistically, we demonstrate that ferroptosis suppressor protein-1 (FSP1) reduces oxidized vitamin K to its hydroquinone form, thus driving a novel non-canonical vitamin K cycle that potently suppresses ferroptosis in cells and mice. We further show 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.
Original publication:
Mishima, E. et al. (2022). A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature
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