Shining a New Light on Ferroptosis

Explore how ferroptosis spreads between cells and the implications for future medical therapies targeting GPX4.

Researchers at the Max Planck Institute of Biophysics and the University of Cologne developed a new optical tool to study ferroptosis, a form of iron-driven cell death. Better understanding of how it spreads could open doors to new therapies.

Text: Pamela Ornelas

Just like iron rusts when exposed to oxygen, our cells can also “rust” from the inside out. This cellular rusting is caused by unstable oxygen-containing molecules that can damage essential parts of the cells. Iron plays a key role in this process by sparking toxic chemical reactions that oxidize fats in cell membranes, a process known as iron-driven lipid peroxidation. When damage goes too far, cells collapse in a type of regulated cell death called ferroptosis.

Ferroptosis isn't always a bad thing. A controlled amount of lipid peroxidation can help cells regulate growth or respond to stress. But excessive ferroptosis has been linked to a range of diseases, including neurodegeneration, kidney failure, and stroke. Cells count with protection mechanism to keep lipid peroxidation in balance. One of the key defenders is a natural antioxidant enzyme called GPX4. GPX4 neutralizes toxic lipid peroxides before they can spread and damage the cellular membrane. If GPX4 is missing or blocked, the cell loses its last line of defence and becomes vulnerable to ferroptosis.

Interestingly, some aggressive cancer cells exploit this vulnerability. They use ferroptosis during metastasis and become heavily dependent on GPX4 to survive. Blocking GPX4 in these cells may tip the balance and trigger their self-destruction, making GPX4 a promising therapeutic target.

In order to explore this, researchers at the Max Planck Institute of Biophysics and the University of Cologne, led by Prof. Ana García-Sáez, developed a new light-controlled system to induce ferroptosis. This tool, called Opto-GPX4Deg, allows precise degradation of GPX4 in specific cells by shining light on them to study ferroptosis propagation. Using Opto-GPX4Deg, the team saw an increase in lipid oxidation and cell death, not only in the activated cells but also in neighboring, untreated cells. Remarkably, once ferroptosis started, the bystander cells could also spread lipid oxidation to their neighbors. However, when cell-to-cell contact was disrupted or free iron was removed, propagation stopped.

The study by Röck et al., recently published in Nature Communications, offers new insights into how ferroptosis spreads in tissues. Using Opto-GPX4Deg to trigger ferroptosis with high precision, the authors demonstrated that the propagation of this cell death process can be blocked both genetically and with drugs, highlighting its potential as a therapeutic target.