When free radicals become uncontrollable and destroy the protective cell membrane in a chain reaction, a cell dies of ferroptosis. When healthy cells are subjected to oxidative stress, they are occasionally damaged.

Cancer cells, in particular, are vulnerable to ferroptosis due to their highly active metabolism, but many of them escape this fate. Researchers around the world are looking for the factors that make a cell susceptible or resistant to ferroptosis so that they can potentially influence this type of cell death therapeutically, according to a study.

Researchers at the German Cancer Research Center, led by Tobias Dick, have discovered a novel mechanism by which cells protect themselves from ferroptosis. The findings of the study were published in the journal Nature Chemical Biology.

It has only recently become known that human cells can produce so-called persulfides from the sulfur-containing amino acid cysteine. These small molecules are characterised by a group of two sulfur atoms and one hydrogen atom. However, the importance of persulfides inside the cell was mysterious from the beginning and remained unknown.

Uladzimir Barayeu of DKFZ, the first author of the current publication, observed that cells boost their production of persulfides as soon as they are stressed by radicals and are at risk of ferroptosis cell death. This was the first indication that cells try to protect themselves with persulfides.

The research team showed that persulfides efficiently suppress membrane damage and ferroptosis and also disclosed the mode of action of these molecules: Persulfides proved to be highly efficient radical scavengers.

They interrupt the destructive chain reaction that threatens the integrity of the cell membrane. The action of persulfides is based on an unusual chemical mechanism. When a persulfide encounters a free radical, it takes on its radical character, thus becoming a radical itself. But the new radical behaves in an unusual way.

Unlike other radicals, it is extremely inert and incapable of causing damage. It reacts exclusively with itself and produces persulfides again in a subsequent reaction. This means that persulfides hardly consume themselves in the elimination of free radicals.

Therefore, even a very low concentration of persulfides can effectively eliminate a much higher concentration of radicals, as the researchers found to their surprise.

The Heidelberg scientists also showed that a cell's ferroptosis sensitivity depends on certain enzymes of sulfur metabolism that generate persulfides.

"Our new results could open up completely new starting points for attacking the internal resistance of cancer cells, for example by pharmacological inhibitors of the enzymes responsible for persulfide production," says Tobias Dick, senior author of the current publication.