The study is published in the current issue of the journal ‘Nature Cell Biology’.
Ferroptosis is a recently recognized form of regulated necrosis. Up until now, this form of cell death has only been thought to be a possible therapeutic approach to treat tumour cells. Yet, ferroptosis also occurs in non-transformed tissues as demonstrated by this study, thus implicating this cell death pathway in the development of a wide range of pathological conditions. More specifically, the deletion of the ferroptosis-regulating enzyme Gpx4* in a pre-clinical model results in high ferroptosis rates in kidney tubular epithelial cells causing acute renal failure.
Specific lipid oxidation offers a pharmacological approach
The international team of scientists, led by the Helmholtz Zentrum München (HMGU)** in cooperation with Cardiff University (UK), the University of Pittsburgh (USA), Columbia University (USA), Karolinska Institute (Sweden), Ludwig-Maximilians-Universität München and Universität Regensburg, has now been able to unravel important molecular mechanisms that drive ferroptosis signaling. “Specific lipid oxidation events take place in ferroptosis,” explains study leader Dr. Marcus Conrad from the HMGU. “We were able to use this signal chain for pharmacological intervention and consequently to protect cells and tissues.”
Liproxstatin-1: a very promising drug candidate
The scientists have identified inhibitors that arrest the ferroptosis process. One such ferroptosis inhibitor is Liproxstatin-1. In the present study, the team was able to show that Liproxstatin-1 suppresses ferroptosis both in human kidney cells, Gpx4 deletion-induced acute renal failure and in a pre-clinical model of hepatic ischemia reperfusion injury. Future invetsigations should shed light into the precise mechanism of action of Liproxstatin-1 in ferroptotic signaling.
Ferroptosis may play a role in various pathological settings. In addition to ischaemic tissue damage, seen for example in renal failure, stroke or cardiovascular diseases, the mechanism may also play a central role in neurodegenerative diseases and in comorbidities of diabetes mellitus. First author and Humboldt fellow at the HMGU, Dr. Jose Pedro Friedmann Angeli sums it up as follows: “Our data show that we can use pharmacological approaches to stop this form of regulated cell death. As a consequence, ferroptosis inhibitors open up novel therapeutic opportunities to mitigate diseases previously thought to be untreatable.”
* Glutathione Peroxidase 4
** At the HMGU, the Institute of Developmental Genetics, the Institute of Pathology and the Institute of Clinical Molecular Biology and Tumor Genetics are involved in the work.
Angeli, J.P.F. et al. (2014), Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nature Cell Biology, doi: 10.1038/ncb3064
The Human Frontier Science Program (HFSP) was one of the groups funding the work. More information on HFSP research funding for the Helmholtz Zentrum München
The Helmholtz Zentrum München, as the German Research Center for Environmental Health, pursues the objective of developing personalized medicine for the diagnosis, therapy and prevention of wide-spread diseases such as diabetes mellitus and lung diseases. To this end, it investigates the interactions of genetics, environmental factors and lifestyle. The Zentrum’s headquarters is located in Neuherberg in the north of Munich. The Helmholtz Zentrum München employs around 2,200 people and is a member of the Helmholtz Association, which has 18 scientific-technical and biological-medical research centres with around 34,000 employees. _______________________________________________________________________________
Dr. Marcus Conrad, Helmholtz Zentrum München – German Research Center for Environmental Health (GmbH), Institute of Developmental Genetics, Ingolstädter Landstr. 1, 85764 Neuherberg – Phone: 089-3187-4608 – Email