The work of the Raphaël Rodriguez team gradually lift the veil on the involvement of iron in cancer biology. A few years ago, the Parisian team demonstrated that certain cancer cells are developing a real iron bulimia. This metal addiction has its origin in the essential role played by iron in the activation of different programs allowing these cells to adapt and, in a way, to become stronger. Thus, the increased capture and use of iron constitute a characteristic feature of the most aggressive cancer cell contingents, those which develop resistance to conventional treatments as well as the ability to migrate to form secondary tumors, metastases.
Risk -free addiction
Notwithstanding this vital character, iron can also be fatal … Indeed, iron overload makes cancer cells more vulnerable to ferroptosis: a particular type of regulated cell death* In which the accumulation of metal leads to a series of reactions ultimately leading to the degradation of the membranes which maintain cellular integrity. If the exploitation of this vulnerability of cancer cells is an attractive therapeutic track, its realization requires a fine understanding of the mechanisms that trigger and control ferroptosis.
The lysosome: where the iron sits
And precisely, the latest works published by Raphaël Rodriguez and his co -authors mark a major advance in this understanding. Experts in the study of the living by means of the tools of chemistry (See box below), the researchers surveyed different types of cancer cells to understand where and how ferroptosis is triggered. Their results designate iron located in lysosomes*compartments of the cell essential to its maintenance, such as the initiation site of ferroptosis. In these organelles, iron catalyzes the production of different very reactive oxidizing compounds which attack the cell membranes made up of lipids. During ferroptosis, this reaction then spreads in cascade until the degradation of the Plasma membrane* causing the death of the cell.
-Ferroptosis at will!
Based on this result, the team designed a new class of small molecules, which they called “phospholipid degrees”, capable of activating ferroptosis. The particular structure of these molecules allows them both to target the plasma membrane, to accumulate there and then activate the iron contained in lysosomes to trigger ferroptosis.
The anti-tumor effect of one of these molecules, the fentomycin, or fento1, was evaluated in vitro and in vivo on different models of poor prognosis for conventional treatments and quick to swarm in the body (adenocarcinoma of pancreas, different types of sarcoma, metastatic breast cancer). Results: the activity of fento1 can eradicate in vitro from cancer cells resistant to treatment and significantly reduces tumor growth in animal models of metastatic breast.
Before the rush to iron
All of these results confirms that activation of ferroptosis by means of suitable molecules is a solid track for the development of a new therapeutic strategy that could contribute to the treatment of the most problematic cancer forms. The synthesis of new phospholipid degrees even more effective and easy to produce and, above all, the continuation of the evaluation of this strategy to clinical studies constitute the new stages that will be necessary to cross before the induction of ferroptosis can constitute a tangible therapeutic pathway to conventional treatments.
[1] T. Cañeque, L. Baron, S. Müller et al., Nature 2025, DOI: 10.1038/S41586-025-08974-4
*See lexicon
