Characterization of a novel ferroptosis regulator

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Ferroptosis is a newly identified cell death modality that has attracted overwhelming interest not only for its contribution to pathological conditions, such as ischemia/reperfusion injury and neurodegeneration, but also as an emerging strategy to eradicate hard to treat tumors. Ferroptosis is negatively regulated by glutathione peroxidase 4 (GPX4) by suppressing the process of phospholipid peroxidation. Therefore, initial attempts have been made to pharmacologically target GPX4 in vivo as a mean to trigger ferroptosis in cancer cells, albeit these approaches have yielded so far only moderate results. This is most likely due to our limited knowledge of the processes that ultimately regulate this form of cell death. In this proposal, we start by presenting the results of an unbiased cDNA overexpression screen aiming to identify genes able to fully complement the loss of GPX4. This approach allowed us to identify a yet-unrecognized oxidoreductase which fully prevents ferroptosis induced by GPX4 deletion or pharmacological inhibition. In this project, we thus aim to characterize how this enzyme is able to bypass the requirement for GPX4 on the molecular level. We will take advantage of a series of state-of-the art methodologies including CRISPR/Cas technology, metabolomics, (oxi) lipidomcis and chemical biology to shed light into the mechanistic details of this novel ferroptosis regulator. Moreover, the in vivo relevance of this pathway will also be assessed through the characterization of two novel mouse models based on the constitutive deletion or the conditional, tissue-specific overexpression of this oxidoreductase. We are convinced that the data generated here will essentially provide a better understanding of the metabolic liabilities sensitizing cells to ferroptosis. In addition, new opportunities will be uncovered to efficiently target this form of cell death with the ultimate goal to identify novel strategies to eradicate cancer cells resistant to standard therapy.