Scientists Discover a Metabolic Switch That Regulates Ferroptosis

The loss of an enzyme can reprogram cellular metabolism in a way that protects cells from a specific form of cell death. Paradoxically, the presumed blockade of this enzyme has the opposite effect.

Switching off an enzyme that plays an important role in sugar metabolism – glycolysis – would normally be expected to cause serious problems for cells. Surprisingly, the opposite is true as well: cells can become highly resistant to a specific form of cell death known as ferroptosis.

Unexpectedly, however, pharmacological inhibition of this enzyme using a special inhibitor produces the exact opposite effect: the intervention makes the cells more susceptible to cell death. The reason is that the inhibitor acts as a pharmacological "double agent." While it blocks the enzyme on the one hand, it simultaneously attacks another important protective protein. As a result, the cell loses one of its key defense mechanisms and dies.

These are the central findings of a new study conducted by researchers at the Julius-Maximilians-Universität Würzburg. The study was led by Antje Gohla, Professor of Biochemical Pharmacology at the Chair of Pharmacology and Toxicology. The team has now published its findings in the journal Science Advances.

An Important Player in Neurodegenerative Diseases and Cancer

In medical research, ferroptosis has increasingly moved into the spotlight in recent years. Ferroptosis is an iron-dependent, oxidative process that destroys cellular stability. Since several tumors – particularly highly aggressive, therapy-resistant tumors – are sensitive to this mechanism, ferroptosis is regarded as a promising target for new therapeutic approaches. In neurodegenerative diseases or tissue damage, however, the opposite strategy applies: in these cases, ferroptosis causes excessive damage and the goal is to prevent this type of cell death in order to better protect the cells.

The team led by Antje Gohla may now have identified a possible molecular switch involved in this process.

"Our investigations initially focused on the enzyme phosphoglycolate phosphatase (PGP)," the pharmacologist explains. Under normal conditions, PGP ensures the smooth progression of glycolysis. The current study shows, however, that the absence of PGP unexpectedly makes cells more resistant to ferroptosis.

This protection is based on what is known as metabolic rewiring – a fundamental reprogramming of cellular metabolism." 

Antje Gohla, Professor of Biochemical Pharmacology, Chair of Pharmacology and Toxicology, Julius-Maximilians-Universität Würzburg

As a consequence of this rewiring, the cell profoundly reorganizes its metabolism. Through several intermediate steps, glucose flux is redirected, allowing the cell to maximize the production of protective antioxidants. As a result, "PGP-deficient cells" become significantly more resistant to oxidative stress.

A Paradoxical Discovery

In search of compounds capable of actively triggering this process, Gohla and her team focused on the substance CP1. In an earlier study, they had already identified it as the world's first experimental PGP inhibitor. The compound CP1 – short for Compound 1 – therefore appeared to be the ideal tool for their experiments.

The paradoxical discovery was that when the researchers applied CP1, exactly the opposite of the expected effect occurred: instead of protecting the cells, the compound made them far more susceptible to cell death. Detailed analyses ultimately revealed CP1 to be a pharmacological "double agent." "CP1 not only blocks PGP, but simultaneously attacks the important protective protein FSP1," Gohla explains.

CP1 uses a particular mechanism to achieve this effect: it causes the protective protein to aggregate into clumps. As a result, FSP1 likely loses its position at the cell membrane and can no longer perform its protective function. The cell consequently loses one of its most important defense mechanisms and dies.

Molecular Basis for New Approaches in Cancer Therapy

The discovery of the dual inhibition of PGP and FSP1 opens up strategic options for the development of future drugs. In particular, this approach may hold potential for tumors that are highly dependent on sugar metabolism – so-called highly glycolytic tumors – and that often exhibit resistance to conventional therapies. The new findings could therefore provide a molecular basis for future combination therapies aimed at more precisely manipulating the balance between cell protection and cell death.