Interview with Prof. Marcus Conrad and Prof. José Pedro Friedmann Angeli: "Effective collaboration depends on honest discussions and being willing to challenge each other’s ideas."

Prof. Conrad, you´ve described a new mechanism of cell death, which is now regarded as a promising approach in cancer therapy: When did you realise that you had uncovered something completely new?

Conrad: As early as my PhD work approximately 25 years ago, while studying the mechanisms of redox stress in cell death and cell cycle progression, we made the unexpected finding that the genetic loss of a specific professional redox enzyme, known as glutathione peroxidase 4 (GPX4), causes a novel form of cell death that does not fit classical frameworks such as apoptosis. This form of cell death does not involve caspase activation but instead is driven by detrimental lipid peroxidation. Accordingly, it can be prevented by vitamin E, nature’s premier radical scavenger in lipid membranes. Using genetic cell and animal models, we were also able to provide strong and early evidence that this cell death paradigm is not merely a cell culture artefact but is also highly relevant in whole organisms, as the loss of GPX4 in neurons causes seizures, ataxia, and early neurodegeneration.

We further found that depleting cells of intracellular glutathione, the main cofactor for numerous cell-protective enzymes, is sufficient to phenocopy the effects of GPX4 deletion alone, indicating that both GPX4 and glutathione are essential for this cell-protective effect. Moreover, by studying the upstream mechanisms regulating glutathione, we discovered that the cysteine–glutamate antiporter system xc-, including xCT (also known as SLC7A11), is an important upstream component of this “yet-unrecognized cell death pathway,” which was later iconically coined ferroptosis in 2012.

Prof. Friedmann Angeli, how would you explain this mechanism of ferroptosis to a non-scientific audience?

Friedmann Angeli: I often compare ferroptosis to an avocado exposed to oxygen. When you cut open an avocado and leave it on the kitchen table, it quickly browns because oxygen damages its fats. A similar process can occur in our cells: their membranes contain fats, and if these fats are no longer protected, they become oxidized, causing the cell membrane to lose its integrity. Ferroptosis is this type of lethal lipid damage in a cell, a regulated process driven by iron and membrane oxidation. Normally, cells have defense mechanisms like GPX4 and FSP1 that help prevent this from happening too easily.

And why are treatment-resistant tumours particularly sensitive to ferroptosis?

Conrad: One important point is that we were likely among the first to directly connect therapy-resistant cancer states with ferroptosis sensitivity. In our study, we identified ACSL4, an enzyme involved in the metabolism of polyunsaturated fatty acids (PUFAs), as an essential determinant of ferroptosis in cancer cell lines. We found that therapy-resistant cells often adopt a membrane composition enriched in polyunsaturated fatty acids, a state that is frequently associated with higher ACSL4 expression. This is particularly relevant because PUFAs are especially prone to oxidative damage, which makes these cells much more susceptible to ferroptosis. We showed this specifically in triple-negative breast cancer models that had become resistant to therapies targeting mitogen signaling. What remains unclear is whether this enrichment in PUFAs is functionally required for the resistant state, or whether it is instead an unintended consequence of the genetic programs that drive therapy resistance, which are often linked to the transcription factor ZEB1. This work was soon followed by a series of major studies that connected the same vulnerability more broadly to epithelial-to-mesenchymal transition. So in a way, the very transcriptional that helps tumors survive treatment may also expose a new therapeutic Achilles’ heel.

You have also developed substances capable of specifically activating ferroptosis – how far away is this approach from being used in humans, and for which types of cancer might it potentially be used?

Friedmann Angeli: I would say that we are still in a relatively early translational phase. Although many of the known ferroptosis inducers, targeting different aspects of the cell death pathway such as GPX4 and the cystine–glutamate antiporter, efficiently trigger ferroptosis in a cellular context, they fail to do so in an organismal setting. This is mostly due to insufficient metabolic stability of these small-molecule compounds, as well as redundancies among different systems that can bypass the inhibition of a single pathway, particularly in vivo.

Nonetheless, our development of sufficiently stable inhibitors of ferroptosis suppressor protein 1 (FSP1), the second most important ferroptosis surveillance system, has shown that these compounds can impair tumor growth in animal models of lung adenocarcinoma, the leading cause of death among cancer patients.

Moreover, we have explored alternative ways to inhibit FSP1 activity and recently demonstrated that interfering with riboflavin metabolism can sensitize tumor cells to ferroptosis. We also showed that roseoflavin can trigger ferroptosis in cancer models, although this approach may require further development before it can be applied in routine clinical oncology.

Beyond lung adenocarcinoma, tumors of particular interest in the context of ferroptosis are those characterized by an increased abundance of PUFAs in cell membranes, as this has been shown to create a specific vulnerability. These include, for instance, MYCN-amplified neuroblastoma and, more broadly, tumor types that become drug-tolerant, metastatic, or highly plastic. The challenge now is to identify the right patients and to develop therapies that are sufficiently potent and selective for safe use in humans.

You both have been working together successfully for many years – what makes your scientific partnership so special?

Friedmann Angeli and Conrad: What defines it, first and foremost, is a shared scientific curiosity, passion, and dedication, along with an equal level of rigor when it comes to mechanistic understanding. We have worked together on ferroptosis for many years, from its early characterization to questions in cancer biology and therapeutic translation, which has built a strong foundation of trust. At the same time, effective collaboration also depends on complementarity, bringing different perspectives, engaging in honest discussions, and being willing to challenge each other’s ideas constructively. I think that the combination of shared vision and productive friction is what has made the partnership strong.

Thank you very much for the interview.