99 Scientists have developed a new small-molecule drug that targets iron in cancer cells, opening a potential path for treating hard-to-reach and drug-resistant tumours. The treatment, known as Fento-1, activates a type of cell death called ferroptosis by unlocking the destructive power of iron stored in cell lysosomes. The findings were published in the journal Nature. Ferroptosis is a form of cell death triggered by the oxidation of cell membrane lipids, a process heavily influenced by iron. While it has been known that iron plays a role in this pathway, the precise location and mechanism of its activity within cancer cells remained elusive. Now, research led by Raphaël Rodriguez at Institut Curie has identified lysosomal iron as a key switch for initiating ferroptosis. The study, recently published in Nature, shows how Fento-1 exploits this mechanism to kill aggressive cancer cells. The research team designed Fento-1 by combining two components: a natural product called marmycin that localises at the plasma membrane, and a synthetic ligand that catalyses iron oxidation under acidic conditions found in lysosomes. Once inside the cell, the compound drives the formation of reactive oxygen species which attack the phospholipid bilayer of cell membranes, ultimately causing the cell to die. This approach has shown promise against drug-tolerant persister cells, a subtype of cancer cells that evade standard treatments and often drive recurrence and metastasis. These cells typically carry high levels of the iron-transporting protein CD44, which increases their susceptibility to Fento-1. In both laboratory and animal models, Fento-1 successfully reduced tumours, especially those rich in CD44-expressing cells such as pancreatic cancer and sarcomas. In treated mice, Fento-1 slowed tumour progression and extended survival without noticeable toxicity. The drug was administered directly into the lymphatic system, a strategy that proved particularly effective in targeting intranodal metastases. Further analysis confirmed that Fento-1-induced ferroptosis was specific to cancer cells with high iron content and could be counteracted by known ferroptosis inhibitors. The study also found that after sublethal doses of Fento-1, some cancer cells entered a new state with reduced iron uptake and increased resistance to ferroptosis. This discovery suggests that while Fento-1 is potent, cancer cells may adapt over time, underscoring the need for combination strategies or dosage optimisation. The findings position lysosomal iron not only as a critical regulator of cell death but also as a viable drug target in treatment-resistant cancers. By fine-tuning this mechanism, researchers hope to develop more effective therapies that exploit cancer’s own metabolic vulnerabilities.