Coordination Funds

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Recent studies have identified metabolic networks and signalling pathways that control previously unrecognised regulated cell death modalities. Among these is ferroptosis, a prevalent and disease-relevant form of cell death characterised by specific metabolic constraints and an iron-dependent accumulation of lipid hydroperoxides. The regulatory elements of ferroptosis have been shown to be associated with several cellular metabolic processes, including those of polyunsaturated fatty acid (PUFAs) metabolism, mevalonate pathway, Krebs cycle, iron handling and cysteine/glutathione (GSH) metabolism. These central metabolic pathways converge on the pivotal importance of the selenoenzyme glutathione peroxidase 4 (GPX4), which is today regarded as the key regulator of ferroptosis, due of its unique function to efficiently reduce peroxides in PUFAs contained in phospholipid bilayers. Emerging evidence suggests that ferroptosis is likely an ancient form of cell death and an evolutionary conserved mechanism that when dysfunctional renders cells susceptible to premature cell death. Moreover, this highly complex cell death pathway has been found to contribute to various pathological conditions. These findings have stimulated a growing need to understand the underlying genetic and metabolic determinants that regulate ferroptosis in order to provide new avenues for their modulation in a therapeutic context. The collaborative actions of the groups associated with the SPP will aim to understand the underlying intricate transcriptional and metabolic networks in relevant model systems on different levels, ranging from basic mechanisms to pre-clinical concepts. We further strive to translate the knowledge gained from biochemical, cellular and pharmacological model systems to an organismal level in mice and men. A deeper understanding of these regulatory networks will ultimately offer the possibility to interfere with this process in the context of cancer treatment as well as in the prevention or treatment of degenerative conditions where ferroptosis plays a central role.