SPP 2306:  Ferroptosis: from Molecular Basics to Clinical Applications

• Subject Area: Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 441859899

Ferroptosis is a widespread and disease-relevant form of cell death characterized by specific metabolic constraints and uncontrolled iron-dependent (phospho)lipid peroxidation. The regulatory processes of ferroptosis have been shown to be associated with several cellular metabolic cues, including polyunsaturated fatty acid (PUFA) metabolism, the mevalonate pathway, the Krebs cycle, iron handling and cysteine/glutathione (GSH) metabolism. These important metabolic pathways converge in the central importance of the selenoenzyme glutathione peroxidase 4 (GPX4), which is considered the guardian of ferroptosis due to its unique activity of efficiently reducing peroxides in PUFAs contained in phospholipid bilayers. Since markers of lipid peroxidation have been detected in numerous pathological conditions such as tissue ischemia/reperfusion injury (IRI), neurodegeneration and liver intoxication, ferroptosis may underlie a large number of degenerative disease conditions. On the contrary, the identification of various pharmacologically amenable nodes, such as the cystine-glutamate amino acid antiporter system xC-, GPX4, ferroptosis suppressor protein-1 (FSP1), dihydrofolate reductase (DHFR), GTP cyclohydrolase (GCH1) and 7- dehydrocholesterol reductase (DHCR7), may provide new opportunities for the induction of ferroptosis in the context of certain malignancies. During the first funding period, members of this consortium have made significant and seminal contributions to this rapidly expanding and exciting field of research. The collaborative actions of the groups associated with the SPP will continue to unravel the underlying complex transcriptional and metabolic networks in relevant model systems at different levels, ranging from basic mechanisms including novel regulators of ferroptosis, the chemical process of lipid peroxidation, metabolic rewiring, the role of iron, the identification of novel small molecule modulators of ferroptosis and potential biomarkers to pre-clinical proof-of-concept models. In addition, the SPP 2306 strives to translate the knowledge gained in the first funding period from biochemical, cellular and pharmacological model systems to the organismal level in mice and humans. A deeper understanding of these regulatory networks will ultimately provide the opportunity to intervene in this cell death process in the context of cancer treatment and organ damage as well as in the prevention or treatment of degenerative diseases in which ferroptosis plays a central role.

• DFG Programme: Priority Programmes

Projects

• Characterization and exploitation of novel ferroptosis regulators to target MYCN amplified cancers (Applicant Trumpp, Ph.D., Andreas )
• Coordination Funds (Applicant Conrad, Marcus )
• cPLA2α-mediated ferroptosis regulation in small cell lung cancer (SCLC) (Applicant von Karstedt, Silvia )
• Crosstalk between ferroptosis and sarmoptosis (Applicant Methner, Axel )
• Deciphering the link between proteostatic control by the ubiquitin-proteasome system and ferroptosis in lymphocytes (Applicants Al Abdulla, Ph.D., Ruba ;  Krüger, Elke Beate )
• Dynamics of lipid metabolism in ferroptosis (Applicant Thiele, Christoph )
• Exploring selenocysteine metabolism as a targeted therapy approach in cancer (Applicant Alborzinia, Ph.D., Hamed )
• Ferroptosis induction as a novel treatment concept for relapsed childhood cancers (Applicant Westermann, Frank )
• Ferroptosis induction as a novel treatment concept for relapsed childhood cancers (Applicant Westermann, Frank )
• Harnessing ferroptosis as a potential therapeutic target against melanoma-associated central nervous system metastases (Applicant Todoran née Stejerean, Ioana )
• Harnessing the immunogenic potential of ferroptosis to improve immunotherapy in liver cancer (Applicant Hammerich, Linda )
• How ferroptosis and ferroptosis-response-pathways shape the immune landscape in pancreatic ductal adenocarcinoma (PDAC) (Applicant Lüdde, Ph.D., Tom )
• Iron-induced pancreatic ferroptosis: Deciphering underlying mechanisms and clinical implications for iron overload disorders (Applicant Muckenthaler, Martina )
• Macrophages in sensing and executing ferroptosis (Applicants Brüne, Bernhard ;  Fuhrmann, Dominik )
• Mechanisms of ferroptosis resistance in brown adipose tissue (Applicant Bartelt, Alexander )
• Metabolic networks supporting FSP1 function and their relevance in ferroptotic cell death (Applicants Conrad, Marcus ;  Friedmann Angeli, José Pedro )
• Modulation of ferroptosis sensitivity by altered lipid metabolism in cancer (Applicant Schulze, Almut )
• Molecular Exploitation of Amyloid Precursor Protein as Novel Ferroptosis Regulator (Applicant Venkataramani, Vivek )
• Neuro-glial crosstalk during ferroptosis (Applicant Conrad, Marcus )
• Potentiating ferroptosis as treatment of allergic airway inflammation (Applicant Wilhelm, Ph.D., Christoph )
• Regulation of ferroptosis in type-2 immune responses (Applicant Esser-von Bieren, Julia )
• Regulators of inflammation-induced ferroptosis in neurons (Applicants Friese, Manuel A. ;  Woo, Marcel Seungsu )
• Relevance of ferroptosis and its therapeutic potential during acute liver injury and hepatocellular carcinoma formation (Applicant Otto, Tobias )
• Role and regulation of subcellular membrane lipid peroxidation in ferroptosis (Applicant Dick, Tobias )
• Role of cells and tissues microenvironment in lipid metabolism and signaling in ferroptosis (Applicant Fedorova, Maria )
• Role of Metabolism-induced Ferroptosis Following Solid Organ Transplantation and its Implication for Allograft Survival (Applicants Eurich, Dennis ;  Kotsch, Ph.D., Katja )
• Selenium metabolism and its contribution to ferroptosis resistance (Applicant Friedmann Angeli, José Pedro )
• Steroid Hormones as Regulators of Ferroptosis Sensitivity During Acute Kidney Injury (Applicant Linkermann, Andreas )
• Substitutive Chemotypes as Tools for the Selective Induction of Ferroptosis in Cancer Cells (Applicant Konrad, David )
• The role of PGE2 production by ferroptotic cancer cells for regulation of anti-cancer T cell immunity (Applicant Böttcher, Jan Philipp )
• The wave of death: ferroptosis propagation from single cell death to tissue damage (Applicant Garcia Sáez, Ana Jesús )
• Understanding dynamics of lipid metabolism and oxidation in ferroptotic cell death programme (Applicant Fedorova, Maria )
• Understanding the mechanisms of ferroptosis in direct neuronal reprogramming – towards improving neuronal replacement in vivo (Applicant Götz, Magdalena )
• Zeb1-mediated mechanisms of the EMT-associated ferroptosis sensitivity (Applicants Brabletz, Thomas ;  Brabletz, Simone )

• Spokesperson: Dr. Marcus Conrad