FRIEDMANN ANGELI Gruppe

Cell death is an inherent and essential aspect of life. This crucial cellular event is maintained by a finely tuned balance between cell survival and cell death which, when disrupted, has been linked to pathological conditions such as neurodegenerative disorders and carcinogenesis. Cell death modalities were broadly divided into programmed and accidental, which later came to be known as apoptosis and necrosis, respectively. This concept overlooked the emerging notion that necrotic forms of cell death are in fact regulated and kept in check by defined survival pathways.

Cell death pathway

Among these regulated necrotic cell death modalities considerable attention has been given to ferroptosis, a cell death pathway that requires phospholipid peroxidation. Our previous work has helped to characterize this pathway where we identified glutathione peroxidase 4 (Gpx4) as an essential regulator of this pathway. Moreover, we shed light into critical metabolic requirements linked to lipid metabolism that determines sensitivity to ferroptosis. Among our current interest are the discovery and characterization of novel nodes regulating ferroptosis and factors regulating them. In addition, we are pursuing the biochemical events linking phospholipid peroxidation and cell death with a particular interest in the role of lipid-derived electrophiles as potential second messengers. In order to track our goals we rely on a broad array of technologies and collaborations spanning from classical molecular biology and biochemistry, proteomics, CRISPR/Cas9 based screen and engineered cellular models and ultimately in vivo mouse models.

Research goals

Our long term goal is to provide the rationale for novel pharmacological approaches that will enable us to tip the balance between life and death decision made by a cell, knowledge that will ultimately result in previously unforeseen therapeutic opportunities to treat disorders were unregulated cell death is a root cause.

Zhiyi Chen, Alex Inague, Kamini Kaushal, Gholamreza Fazeli, Danny Schilling, Thamara N Xavier da Silva, Ancely Ferreira Dos Santos, Tasneem Cheytan, Florencio Porto Freitas, Umut Yildiz, Lucas Gasparello Viviani, Rodrigo Santiago Lima, Mikaela Peglow Pinz, Isadora Medeiros, Thais Satie Iijima, Thiago Geronimo Pires Alegria, Railmara Pereira da Silva, Larissa Regina Diniz, Simon Weinzweig, Judith Klein-Seetharaman, Andreas Trumpp, Adriana Mañas, Robert Hondal, Christoph Bartenhagen, Matthias Fischer, Briana K Shimada, Lucia A Seale, Thilo Samson Chillon, Marietta Fabiano, Lutz Schomburg, Ulrich Schweizer, Luis E Netto, Flavia C Meotti, Tobias P Dick, Hamed Alborzinia, Sayuri Miyamoto, José Pedro Friedmann Angeli PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance. Molecular Cell 2024 Dec 5;84 (23), 4645-4659. e9.

Juliane Tschuck, Wulf Tonnus, Shubhangi Gavali, Andrea Kolak, Melodie Mallais, Francesca Maremonti, Mami Sato, Ina Rothenaigner, José Pedro Friedmann Angeli, Derek A Pratt, Andreas Linkermann, Kamyar Hadian Seratrodast inhibits ferroptosis by suppressing lipid peroxidation. Cell Death & Disease 2024 Nov 22;15 (11), 853.

Ancély Ferreira dos Santos, José Pedro Friedmann-Angeli Troubling bonds: lipid unsaturation promotes selenium dependency and sensitivity to ferroptosis. EMBO Molecular Medicine 2024 Nov 11;16 (11), 2657-2659.

Alex Inague, Douglas H Nakahata, Lucas G Viviani, Thiago GP Alegria, Rodrigo S Lima, Thais S Iijima, Luís Eduardo S Netto, José Pedro F Angeli, Sayuri Miyamoto, Raphael EF de Paiva On the binding of auranofin to Prdx6 and its potential role in cancer cell sensitivity to treatment. Free Radical Biology and Medicine 2024 Nov 1;224, 346-351.

Annemarie Schwab, Zhigang Rao, Jie Zhang, André Gollowitzer, Katharina Siebenkäs, Nino Bindel, Elisabetta D’Avanzo, Ruthger van Roey, Yussuf Hajjaj, Ece Özel, Isabell Armstark, Leonhard Bereuter, Fengting Su, Julia Grander, Ehsan Bonyadi Rad, Arwin Groenewoud, Felix B Engel, George W Bell, Whitney S Henry, José Pedro Friedmann Angeli, Marc P Stemmler, Simone Brabletz, Andreas Koeberle, Thomas Brabletz Zeb1 mediates EMT/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition. Nature Cell Biology 2024 Sep;26 (9), 1470-1481.

Hamed Alborzinia, José Pedro Friedmann Angeli Iron: The Secret Ingredient Breaking PARPi Resistance. Cancer Discovery 2024 Aug 2;14 (8), 1372-1374.

Rebecca Holzapfel, Agata Prell, Fabian Schumacher, Veronika Perschin, José Pedro Friedmann Angeli, Burkhard Kleuser, Christian Stigloher, Gholamreza Fazeli Degradation of hexosylceramides is required for timely corpse clearance via formation of cargo-containing phagolysosomal vesicles. European Journal of Cell Biology 2024 Jun 1;103 (2), 151411.

Carsten Berndt, Hamed Alborzinia, Vera Skafar Amen, Scott Ayton, Uladzimir Barayeu, Alexander Bartelt, Hülya Bayir, Christina M Bebber, Kivanc Birsoy, Jan P Böttcher, Simone Brabletz, Thomas Brabletz, Ashley R Brown, Bernhard Brüne, Giorgia Bulli, Alix Bruneau, Quan Chen, Gina M DeNicola, Tobias P Dick, Ayelén Distéfano, Scott J Dixon, Jan B 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 Gu, Linda Hammerich, Behrouz Hassannia, Xuejun Jiang, Aicha Jeridi, Yun Pyo Kang, Valerian E Kagan, David B Konrad, Stefan Kotschi, Peng Lei, Marlène Le Tertre, Sima Lev, Deguang Liang, Andreas Linkermann, Carolin Lohr, Svenja Lorenz, Tom Luedde, Axel Methner, Bernhard Michalke, Anna V Milton, Junxia Min, Eikan Mishima, Sebastian Müller, Hozumi Motohashi, Martina U Muckenthaler, Shohei Murakami, James A Olzmann, Gabriela Pagnussat, 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 Soula, Benedikt Spitzlberger, Brent R Stockwell, Leonie Thewes, Oliver Thorn-Seshold, Shinya Toyokuni, Wulf Tonnus, Andreas Trumpp, Peter Vandenabeele, Tom Vanden Berghe, Vivek Venkataramani, Felix CE Vogel, Silvia von Karstedt, Fudi Wang, Frank Westermann, Chantal Wientjens, Christoph Wilhelm, Michele Wölk, Katherine Wu, Xin Yang, Fan Yu, Yilong Zou, Marcus Conrad Ferroptosis in health and disease. Redox biology 2024 May 30; 103211 

Thiago C Genaro-Mattos, Zeljka Korade, Namood-e Sahar, Jose Pedro Friedmann Angeli, Károly Mirnics, Eric S Peeples Enhancing 7-dehydrocholesterol suppresses brain ferroptosis and tissue injury after neonatal hypoxia–ischemia. Scientific reports 2024 Apr 4;14 (1), 7924.

Madlen Meinert, Christina Jessen, Anita Hufnagel, Julia Katharina Charlotte Kreß, Mychal Burnworth, Theo Däubler, Till Gallasch, Thamara Nishida Xavier da Silva, Ancély Ferreira Dos Santos, Carsten Patrick Ade, Werner Schmitz, Susanne Kneitz, José Pedro Friedmann Angeli, Svenja Meierjohann Thiol starvation triggers melanoma state switching in an ATF4 and NRF2-dependent manner. Redox Biology 2024 Apr 1;70, 103011.

Anne von Mässenhausen, Marlena Nastassja Schlecht, Kristina Beer, Francesca Maremonti, Wulf Tonnus, Alexia Belavgeni, Shubhangi Gavali, Karolin Flade, Joel S Riley, Nadia Zamora Gonzalez, Anne Brucker, Jorunn Naila Becker, Mirela Tmava, Claudia Meyer, Mirko Peitzsch, Christian Hugo, Florian Gembardt, Jose Pedro Friedmann Angeli, Stefan R Bornstein, Stephen WG Tait, Andreas Linkermann Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis. Science Advances 2024 March 15;10 (11), eadk7329.

Babli Chhillar, Rajni Kadian, Manish Kumar, Manisha Yadav, Nikhil Sodhi, Thamara Nishida Xavier da Silva, Jose Pedro Friedmann Angeli, Vijay P Singh Aminic organoselenium compounds as glutathione peroxidase mimics and inhibitors of ferroptosis. ChemBioChem 2024 Feb 16;25 (4), e202400074.

Florencio Porto Freitas, Hamed Alborzinia, Ancély Ferreira Dos Santos, Palina Nepachalovich, Lohans Pedrera, Omkar Zilka, Alex Inague, Corinna Klein, Nesrine Aroua, Kamini Kaushal, Bettina Kast, Svenja M Lorenz, Viktoria Kunz, Helene Nehring, Thamara N Xavier da Silva, Zhiyi Chen, Sena Atici, Sebastian G Doll, Emily L Schaefer, Ifedapo Ekpo, Werner Schmitz, Aline Horling, Peter Imming, Sayuri Miyamoto, Ann M Wehman, Thiago C Genaro-Mattos, Karoly Mirnics, Lokender Kumar, Judith Klein-Seetharaman, Svenja Meierjohann, Isabel Weigand, Matthias Kroiss, Georg W Bornkamm, Fernando Gomes, Luis Eduardo Soares Netto, Manjima B Sathian, David B Konrad, Douglas F Covey, Bernhard Michalke, Kurt Bommert, Ralf C Bargou, Ana Garcia-Saez, Derek A Pratt, Maria Fedorova, Andreas Trumpp, Marcus Conrad, José Pedro Friedmann Angeli 7-Dehydrocholesterol is an endogenous suppressor of ferroptosis. Nature  2024 Feb 8;626 (7998), 401-410.

Ancély Ferreira Dos Santos, Gholamreza Fazeli, Thamara Nishida Xavier da Silva, José Pedro Friedmann Angeli Ferroptosis: mechanisms and implications for cancer development and therapy response. Trends in cell biology 2023 Dec 1;33 (12), 1062-1076.

Toshitaka Nakamura, Eikan Mishima, Naoya Yamada, André Santos Dias Mourão, Dietrich Trümbach, Sebastian Doll, Jonas Wanninger, Elena Lytton, Peter Sennhenn, Thamara Nishida Xavier da Silva, José Pedro Friedmann Angeli, Michael Sattler, Bettina Proneth, Marcus Conrad Integrated chemical and genetic screens unveil FSP1 mechanisms of ferroptosis regulation. Nature structural & molecular biology  2023 Nov;30(11), 1806-1815.

Thamara Nishida Xavier da Silva, José Pedro Friedmann Angeli Sabotaging the breaks: FSEN1 expands the toolbox of FSP1 inhibitors Cell Chemical Biology 2023 Sept 21; 30(9), 1006-1008

Alborzinia H*, Chen Z*, Yildiz U*, Freitas FP, Vogel FCE, Varga J, Batani J, Bartenhagen C, Schmitz W,  Büchel G, Michalke B, Zheng J, Meierjohann S, Girardi E, Espinet E,  Floresz A, Ferreira dos Santos A,  Aroua N, Schlicker L, Xavier da Silva TN, Przybylla A, Zeisberger P, Superti-Furga G, Eilers M, Conrad M, Fischer M, Schulze A, Trumpp A*, Friedmann Angeli JP* Selenocysteine metabolism is a targetable vulnerability in MYCN-amplified cancers Biorxiv: doi: https://doi.org/10.1101/2022.05.17.492172

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. Hydropersulfides inhibit lipid peroxidation and ferroptosis by scavenging radicals. Nat Chem Biol. 2022 Sep 15. doi: 10.1038/s41589-022-01145-w.

Nishida Xavier da Silva T, Friedmann Angeli JP, Ingold I. GPX4: old lessons, new features. Biochem Soc Trans. 2022 Jun 30;50(3):1205-1213.

Doll S*, Freitas FP*, Shah R, Aldrovandi M, da Silva MC, Ingold I, Goya Grocin A, Xavier da Silva TN, Panzilius E, Scheel CH, Mourão A, Buday K, Sato M, Wanninger J, Vignane T, Mohana V, Rehberg M, Flatley A, Schepers A, Kurz A, White D, Sauer M, Sattler M, Tate EW, Schmitz W, Schulze A, O'Donnell V, Proneth B, Popowicz GM, Pratt DA, Angeli JPF*, Conrad M*. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019 Nov;575(7784):693-698. doi: 10.1038/s41586-019-1707-0.

Friedmann Angeli JP, Krysko DV, Conrad M. Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion. Nat Rev Cancer. 2019 Jul;19(7):405-414.­

Ingold I, Berndt C, Schmitt S, Doll S, Poschmann G, Buday K, Roveri A, Peng X, Porto Freitas F, Seibt T, Mehr L, Aichler M, Walch A, Lamp D, Jastroch M, Miyamoto S, Wurst W, Ursini F, Arnér ESJ, Fradejas-Villar N, Schweizer U, Zischka H, Friedmann Angeli JP, Conrad M. Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis. Cell. 2017 Dec 16. pii: S0092-8674(17)31438-1. doi: 10.1016/j.cell.2017.11.048.

Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascón S, Hatzios SK, Kagan VE, Noel K, Jiang X, Linkermann A, Murphy ME, Overholtzer M, Oyagi A, Pagnussat GC, Park J, Ran Q, Rosenfeld CS, Salnikow K, Tang D, Torti FM, Torti SV, Toyokuni S, Woerpel KA, Zhang DD. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell. 2017 Oct 5;171(2):273-285. doi: 10.1016/j.cell.2017.09.021

Angeli JPF, Shah R, Pratt DA, Conrad M. Ferroptosis Inhibition: Mechanisms and Opportunities.Trends Pharmacol Sci. 2017 May;38(5):489-498. doi: 10.1016/j.tips.2017.02.005

Zilka O, Shah R, Li B, Friedmann Angeli JP, Griesser M, Conrad M, Pratt DA. On the Mechanism of Cytoprotection by Ferrostatin-1 and Liproxstatin-1 and the Role of Lipid Peroxidation in Ferroptotic Cell Death. ACS Cent Sci. 2017 Mar 22;3(3):232-243. doi: 10.1021/acscentsci.7b00028.

Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, Irmler M, Beckers J, Aichler M, Walch A, Prokisch H, Trümbach D, Mao G, Qu F, Bayir H, Füllekrug J, Scheel CH, Wurst W, Schick JA, Kagan VE, Angeli JP*, Conrad M*. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017 Jan;13(1):91-98. doi: 10.1038/nchembio.2239.

Kagan VE, Mao G*, Qu F*, Angeli JP*, Doll S, Croix CS, Dar HH, Liu B, Tyurin VA, Ritov VB, Kapralov AA, Amoscato AA, Jiang J, Anthonymuthu T, Mohammadyani D, Yang Q, Proneth B, Klein-Seetharaman J, Watkins S, Bahar I, Greenberger J, Mallampalli RK, Stockwell BR, Tyurina YY, Conrad M, Bayır H. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol. 2017 Jan;13(1):81-90. doi: 10.1038/nchembio.2238.

Conrad M, Angeli JP, Vandenabeele P, Stockwell BR. Regulated necrosis: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2016 May;15(5):348-66. doi: 10.1038/nrd.2015.6.

Gascón S, Murenu E, Masserdotti G, Ortega F, Russo GL, Petrik D, Deshpande A, Heinrich C, Karow M, Robertson SP, Schroeder T, Beckers J, Irmler M, Berndt C, Angeli JP, Conrad M, Berninger B, Götz M. Identification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal Reprogramming. Cell Stem Cell. 2016 Mar 3;18(3):396-409. doi: 10.1016/j.stem.2015.12.003.

Conrad M, Friedmann Angeli JP. Glutathione peroxidase 4 (Gpx4) and ferroptosis: what's so special about it? Mol Cell Oncol. 2015 Jan 30;2(3):e995047. doi: 10.4161/23723556.2014.995047.

Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, Herbach N, Aichler M, Walch A, Eggenhofer E, Basavarajappa D, Rådmark O, Kobayashi S, Seibt T, Beck H, Neff F, Esposito I, Wanke R, Förster H, Yefremova O, Heinrichmeyer M, Bornkamm GW, Geissler EK, Thomas SB, Stockwell BR, O'Donnell VB, Kagan VE, Schick JA, Conrad M. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 2014 Dec;16(12):1180-91. doi: 10.1038/ncb3064.

Supervisor – Biomedicine