The advent of the Iron Age in cell death

ongoing

The recognition of distinct regulated cell death pathways presents tantalizing possibilities for gaining control over life and death decisions made by cells to both prevent age-dependent (neuro)degenerative diseases and to fight cancer. For decades, apoptosis has been considered as the sole form of regulated cell death, while others were deemed unregulated, necrotic. In this context, pioneering work originating from my group enabled to establish “ferroptosis” as an iron-dependent cell death modality that is marked by the oxidative destruction of cellular membranes. Ferroptosis has sparked overwhelming interest in the last few years not only because it harbours many pharmacologically tractable nodes, but as it is likely induced only under pathological conditions, thus opening the unique opportunity for a broad therapeutic window of novel ferroptosis modulators. While some of the molecular players, metabolic contexts and respective small molecule inhibitors and inducers of ferroptosis have been recently described, pivotal questions have remained unanswered. In a holistic approach this project is conceived to tackle these fundamental questions by providing answers to (i) whether there are yet-unrecognized key ferroptosis nodes that may explain why certain cells are highly vulnerable to ferroptosis while others are not, (ii) the nature and subcellular compartment where the initial ferroptosis priming signal is being generated and (iii) why certain cells and tissues die by apoptosis while others succumb to ferroptosis. Successful implementation of the herein proposed aims will yield novel ferroptosis regulating genes as potential future drug targets, decipher and localize the death signal affording the rationale design of refined small molecule ferroptosis modulators and enable the precision-based treatment of patients suffering from early cell loss and tissue demise or cancer.