Redox Signaling & Disease

The discovery of regulated forms of necrotic cell death presents tantalizing possibilities for gaining control over the life and death decisions made by cells in normal tissue homeostasis and in disease. Recent research has uncovered regulatory mechanisms and signaling pathways controlling several different cell death routines including ferroptosis. Ferroptosis has attracted great attention because of its role in a growing number of pathophysiological contexts, such as neurodegeneration, tissue ischemia/reperfusion injury (IRI), early tissue loss and cancer as well as its tractability for pharmacological intervention. Ferroptosis is marked by lethal iron-dependent lipid peroxidation and is clearly distinct from other cell death modalities in cellular, genetic and biochemical terms. Cysteine availability, glutathione (GSH) biosynthesis and proper functioning of the selenoenzyme glutathione peroxidase 4 (GPX4), the key ferroptosis regulator, are at the core of ferroptosis control.

Ingold et all Cell 2018

In this regard, the Conrad laboratory has made several landmark contributions and showed for the first time in 2008 that loss of GPX4 in mice causes a novel non-apoptotic cell death pathway, now known as ferroptosis, and that GPX4 prevents from neurodegeneration. We could further introduce the first in vivo efficacious ferroptosis inhibitor, called liproxstatin-1, discovered in a small molecule high throughput screening campaign performed at Helmholtz Zentrum München. Liproxstatin-1 (being active in the low nanomolar range) not only protects from hepatic ischemia/reperfusion injury and in a genetic model of acute renal failure, but also mitigates neuronal loss in various models of neurodegenerative disease. In close collaboration with the Stem Cell Institute, we could further demonstrate that Liproxstatin-1 boosts direct astrocyte-neuron conversion during neuronal reprogramming. A genome-wide, CRISPR/Cas9-mediated screening approach recently allowed us to identify and characterize the first downstream player in ferroptosis, i.e. acyl-CoA synthetase long-chain family member 4 (ACSL4). Its role in ferroptosis relies on its activity to activate preferably long-chain polyunsaturated fatty acids (PUFAs), which when incorporated into lipid bilayers can undergo lipid peroxidation thereby generating proximate signals of ferroptotic cell death. We could further show that ACSL4 expression predicts sensitivity versus resistance to ferroptosis in a subset of triple negative breast cancer (TNBC) cells.

Current research performed in the Conrad laboratory is geared towards the identification and validation of yet unrecognized ferroptosis players/events in vitro and in vivo, the identification and development of novel ferroptosis modulators and the discovery of metabolic biomarkers, the latter being highly relevant to assess the contribution of ferroptosis to human pathologies.