Gaining control over life and death decisions in cells either affords to prevent (neuro)degenerative diseases or to combat cancer. In this context, ferroptosis, a recently described non-apoptotic cell death modality characterized by an iron-dependent overwhelming lipid peroxidation, is emerging as the root cause of numerous degenerative diseases including neurodegeneration and tissue ischemia/reperfusion injury. Conversely, ferroptosis has been proposed as a pharmacologically tractable vulnerability in therapy-resistant and de-differentiating tumors. Yet, years before the term “ferroptosis” was coined in 2012 our laboratory had shown for the first time that loss of a distinct redox enzyme, namely glutathione peroxidase 4 (GPX4), causes a novel form of non-apoptotic cell death in cells and mice, now generally known as ferroptosis. Meanwhile, we and others have shown that GPX4, along with its cofactor glutathione, is the guardian of ferroptosis. By using genome-wide genetic and pharmacological screens, our group has made several landmark discoveries unraveling all key regulatory nodes of ferroptosis, including acyl-CoA synthetase long-chain family member 4 (ACSL4) and ferroptosis suppressor protein-1 (FSP1). Furthermore, we also introduced the first in vivo efficacious ferroptosis inhibitor liproxstatin-1. Despite these key discoveries, numerous open questions have remained. For instance, it remains unclear whether there are yet-unrecognized powerful ferroptosis suppressive systems beyond GPX4 and FSP1. Besides, there are numerous conflicting reports regarding the subcellular site of an initial ferroptotic death signal. Finally, the genetic and metabolic determinants that eventually decide the cell vulnerability to ferroptosis or other forms of oxidative cell death have remained unclear. Therefore, the research program IRONDEATH aims to tackle these key issues by taking advantage of (i) genome-wide genetic suppressor screens and next-generation antibody-derived tools, (ii) a chemogenetic approach to site-specifically generate oxidative stress signals within cells, and (iii) non-targeted metabolomics and targeted oxidative lipidomics studies in representative transgenic mouse models. Findings obtained in the IRONDEATH program are expected to generate breakthrough discoveries in ferroptosis and cell death in general as they will provide novel concepts for the development of target-based in vivo applicable therapies based on ferroptosis modulation.
