Examination of the interaction between the immune system and regulated necrotic events in terms of ischemia - reperfusion injury in liver transplantation as a basis for the development of new therapeutic approaches.

• Applicants: Professorin Dr. Elke Eggenhofer; Dr. Bettina Proneth
• Subject Area: General and Visceral Surgery
• Term: from 2018 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 406231667

• Final Report Year: 2025

Final Report Abstract

In addition to the organ rejection, transplants also suffers from damage to the organ due to ischemia-reperfusion injury (IRI). In 10-20% of cases, this leads to impaired organ function and early graft failure. This is of highest clinical relevance, as the need for donor organs is far greater than the number of organs available, mainly due to a lack of donor willingness. The situation of the ever-increasing organ shortage and the associated long waiting time makes it necessary to treat available organs by preventing IRI. This means that so-called marginal organs, which carry a higher risk of developing severe IRI (and therefore poorer graft function), could also be used. Since there are currently no drugs to minimize IRI after organ transplantation, there is a high medical need to develop new tissue-protective therapeutic strategies in this area. Several lines of evidence now suggest that ferroptosis - a form of regulated necrotic cell death - is a central cause of many degenerative diseases, including IRI and acute organ failure. Although several hallmarks of this form of cell death have been previously uncovered, the term ferroptosis was first formally introduced in 2012 as a non-apoptotic, metabolic cell death mechanism characterized by excessive, iron-dependent lipid peroxidation. The aim of the DFG-funded project was to investigate the underlying mechanisms of ferroptosis and the resulting necroinflammation in IRI-induced liver damage. It also aimed to clarify the extent to which immune cell activation is linked to ferroptotic cell death. This is particularly important because, to develop a therapy, it is necessary to know whether ferroptosis occurs first and then immune cell activation or vice versa. For this purpose, a combination of transgenic mouse models and a 2nd generation liproxstatin was used. The results from our project clearly show that ferroptosis results from tissue damage and that the infiltration of effector immune cells takes place afterwards. Therefore, the targeted modulation of ferroptosis by specific ferroptosis inhibitors is a promising therapeutic approach for IRI in the context of liver transplantation, but also for the treatment of previously incurable diseases.

Publications

• The different types of cell death: Ferroptosis, myth or reality? Implications for cancer, SFPT, June 14-16, Lille, France, invited talk
  Proneth B.
  
• Augmenter of Liver Regeneration Reduces Ischemia Reperfusion Injury by Less Chemokine Expression, Gr-1 Infiltration and Oxidative Stress. Cells, 8(11), 1421.
  Weiss, Thomas S.; Lupke, Madeleine; Dayoub, Rania; Geissler, Edward K.; Schlitt, Hans J.; Melter, Michael & Eggenhofer, Elke
  
• Selenium: Tracing Another Essential Element of Ferroptotic Cell Death. Cell Chemical Biology, 27(4), 409-419.
  Conrad, Marcus & Proneth, Bettina
  
• Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury. Nature Communications, 12(1).
  Tonnus, Wulf; Meyer, Claudia; Steinebach, Christian; Belavgeni, Alexia; von Mässenhausen, Anne; Gonzalez, Nadia Zamora; Maremonti, Francesca; Gembardt, Florian; Himmerkus, Nina; Latk, Markus; Locke, Sophie; Marschner, Julian; Li, Wenjun; Short, Spencer; Doll, Sebastian; Ingold, Irina; Proneth, Bettina; Daniel, Christoph; Kabgani, Nazanin ... & Linkermann, Andreas
  
• Sorafenib fails to trigger ferroptosis across a wide range of cancer cell lines. Cell Death & Disease, 12(7).
  Zheng, Jiashuo; Sato, Mami; Mishima, Eikan; Sato, Hideyo; Proneth, Bettina & Conrad, Marcus
  
• Steatotic Livers Are More Susceptible to Ischemia Reperfusion Damage after Transplantation and Show Increased γδ T Cell Infiltration. International Journal of Molecular Sciences, 22(4), 2036.
  Eggenhofer, Elke; Groell, Anja; Junger, Henrik; Kasi, Amoon; Kroemer, Alexander; Geissler, Edward K.; Schlitt, Hans J. & Scherer, Marcus N.
  
• Targeting Ferroptosis: New Hope for As-Yet-Incurable Diseases. Trends in Molecular Medicine, 27(2), 113-122.
  Conrad, Marcus; Lorenz, Svenja M. & Proneth, Bettina
  
• A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature, 608(7924), 778-783.
  Mishima, Eikan; Ito, Junya; Wu, Zijun; Nakamura, Toshitaka; Wahida, Adam; Doll, Sebastian; Tonnus, Wulf; Nepachalovich, Palina; Eggenhofer, Elke; Aldrovandi, Maceler; Henkelmann, Bernhard; Yamada, Ken-ichi; Wanninger, Jonas; Zilka, Omkar; Sato, Emiko; Feederle, Regina; Hass, Daniela; Maida, Adriano; Mourão, André Santos Dias ... & Conrad, Marcus
  
• Intrinsic and Extrinsic Limitations to the Design and Optimization of Inhibitors of Lipid Peroxidation and Associated Cell Death. Journal of the American Chemical Society, 144(32), 14706-14721.
  Farmer, Luke A.; Wu, Zijun; Poon, Jia-Fei; Zilka, Omkar; Lorenz, Svenja M.; Huehn, Stephanie; Proneth, Bettina; Conrad, Marcus & Pratt, Derek A.
  
• Liproxstatins: From discovery to clinical applicationIron, Reactive Oxygen Species & Ferroptosis in Life, Death & Disease, AWAJI, Japan, October 10-14 2022, selected talk
  Proneth B.
  
• Integrated chemical and genetic screens unveil FSP1 mechanisms of ferroptosis regulation. Nature Structural & Molecular Biology, 30(11), 1806-1815.
  Nakamura, Toshitaka; Mishima, Eikan; Yamada, Naoya; Mourão, André Santos Dias; Trümbach, Dietrich; Doll, Sebastian; Wanninger, Jonas; Lytton, Elena; Sennhenn, Peter; Nishida Xavier da Silva, Thamara; Angeli, José Pedro Friedmann; Sattler, Michael; Proneth, Bettina & Conrad, Marcus
  
• Phase separation of FSP1 promotes ferroptosis. Nature, 619(7969), 371-377.
  Nakamura, Toshitaka; Hipp, Clara; Santos Dias Mourão, André; Borggräfe, Jan; Aldrovandi, Maceler; Henkelmann, Bernhard; Wanninger, Jonas; Mishima, Eikan; Lytton, Elena; Emler, David; Proneth, Bettina; Sattler, Michael & Conrad, Marcus
  
• Activation of lysosomal iron triggers ferroptosis in cancer. Springer Science and Business Media LLC.
  Rodriguez, Raphaël; Cañeque, Tatiana; Baron, Leeroy; Müller, Sebastian; Carmona, Alanis; Colombeau, Ludovic; Versini, Antoine; Sabatier, Marie; Sampaio, Julio; Mishima, Eikan; Picard-Bernes, Armel; Solier, Stéphanie; Zheng, Jiashuo; Proneth, Bettina; Thoidingjam, Leishemba; Gaillet, Christine; Grimaud, Laurence; Fraser, Cameron; Szylo, Krystina ... & Ubellacker, Jessalyn
  
• Chains of death. Nature Chemical Biology, 20(7), 799-800.
  Zheng, Jiashuo & Proneth, Bettina
  
• Extrahepatic Bile Duct Organoids as a Model to Study Ischemia/Reperfusion Injury During Liver Transplantation. Transplant International, 37.
  Kreiner, P.; Eggenhofer, E.; Schneider, L.; Rejas, C.; Goetz, M.; Bogovic, N.; Brunner, S. M.; Evert, K.; Schlitt, H. J.; Geissler, E. K. & Junger, H.
  
• Ferroptosis in health and disease. Redox Biology, 75, 103211.
  Berndt, Carsten; Alborzinia, Hamed; Amen, Vera Skafar; Ayton, Scott; Barayeu, Uladzimir; Bartelt, Alexander; Bayir, Hülya; Bebber, Christina M.; Birsoy, Kivanc; Böttcher, Jan P.; Brabletz, Simone; Brabletz, Thomas; Brown, Ashley R.; Brüne, Bernhard; Bulli, Giorgia; Bruneau, Alix; Chen, Quan; DeNicola, Gina M.; Dick, Tobias P. ... & Conrad, Marcus
  
• Ferroptosis Inhibition: A Key Opportunity for the Treatment of Ischemia/Reperfusion Injury in Liver Transplantation. Transplantation, 109(5), e228-e236.
  Eggenhofer, Elke & Proneth, Bettina