Scientists unravel molecular mechanisms that drive ferroptosis signaling

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."