Ferroptosis: activating iron to overcome treatment-resistant cancers?

#Ferroptosis #ResistantCancer #LysosomalIron #CD44 #Pancreas #Sarcoma


Aggressive solid tumors, such as pancreatic cancer or certain sarcomas, have a remarkable ability to evade treatment. These cancers often harbor a subset of cells known as “drug-tolerant persister cells” (DTPs), capable of surviving conventional therapies. A Franco-international team has recently uncovered an unsuspected vulnerability: their dependency on iron—specifically, iron stored within lysosomes.

A study led by Raphaël Rodriguez, published in Nature in June 2025, reveals that targeted activation of lysosomal iron triggers ferroptosis, a form of cell death driven by lipid peroxidation. This research paves the way for a novel therapeutic strategy—one that targets not the tumor’s genetics, but its cellular state and iron metabolism.  

Cell death as a therapeutic tool

Ferroptosis is mechanistically distinct from apoptosis. It results from the uncontrolled buildup of oxidized lipids within cell membranes. Iron is a potent catalyst for this chain reaction. In tumors, certain cells accumulate iron in their lysosomes—organelles responsible for cellular degradation—which paradoxically makes them vulnerable to oxidation.

The authors demonstrate that liproxstatin-1, a ferroptosis inhibitor, works by neutralizing iron in lysosomes. Conversely, their custom-designed molecule, Fentomycin-1 (Fento-1), reactivates this iron and initiates the oxidative breakdown of phospholipids, leading to the death of targeted cancer cells.  

CD44 and iron: a toxic duo for cancer cells

A major finding of the study is the identification of a particularly sensitive tumor subpopulation: CD44high cells. This surface marker, linked to cancer stem cells and mesenchymal states, promotes iron endocytosis. As a result, these cells accumulate redox-active iron in lysosomes, making them especially vulnerable to ferroptosis induction by Fento-1.

In human samples of pancreatic cancer and sarcomas, Fento-1 selectively reduced the CD44high population—even after exposure to standard chemotherapies. The remaining cells adopted a more epithelial phenotype, with lower iron content and thus increased resistance to ferroptosis, illustrating adaptive cellular plasticity.  

Impressive preclinical results

• In vitro: Fento-1 induces massive membrane phospholipid oxidation in several human cancer lines (PDAC, sarcomas, triple-negative breast cancer), with 2–3× greater efficacy than classical ferroptosis inducers like RSL3 or erastin. In HT-1080 cells, Fento-1 rapidly increases 4-HNE (a lipid peroxidation marker) and boosts lysophospholipid levels (2× to 5× depending on the species) within 24 hours.
• Ex vivo: In freshly dissociated tumor cells from 13 patients with pancreatic cancer or sarcoma, Fento-1 reduces the CD44high population by ~50% in 24 hours (p < 0.01). This reduction correlates with a significant rise in oxidized lipids (e.g., PCOx36:2, PCOx38:4), averaging 2.5× higher than controls—an effect nullified by liproxstatin-1 or α-tocopherol co-treatment.
• In vivo: In a mouse model of metastatic triple-negative breast cancer (4T1), intralymphatic administration of Fento-1 (3 µg every other day for 15 days) led to a >60% reduction in lymph node tumor volume by day 10 (p = 1.7 × 10⁻⁶), and significantly improved survival (median extended from 20 to 28 days, p = 0.029). The proportion of CD44high cells dropped from ~50% to <15% (p < 0.01), with no change in animal weight—indicating good tolerance.

 

Changing the paradigm: targeting iron, not the genome

This study proposes a paradigm shift in the fight against treatment-resistant cancers. Instead of targeting oncogenic mutations, the strategy leverages a transient metabolic state—lysosomal iron overload. This cellular profile is associated with a mesenchymal state, high plasticity, and resistance to traditional cytotoxic treatments.

Fento-1 could potentially eradicate drug-tolerant persister cells (DTPs) before they re-emerge, or enhance the efficacy of baseline treatments. The researchers also propose using CD44 or iron load as biomarkers to guide the use of such compounds in a precision medicine approach.  

Read next: Ferroptosis: A Key Mechanism in Anti-Androgen Treatments for Prostate Cancer

A promising yet cautious therapeutic pathway

While the results are promising, challenges remain. The effects of Fento-1 on non-tumoral iron-rich tissues are still unknown. Additionally, cellular adaptation to ferroptotic stress suggests that intermittent or combination therapies may be necessary to prevent resistance. A deeper understanding of cell states favoring ferroptosis (e.g., mesenchymal, CD44high, high oxidative stress) will be critical to optimizing this approach.

To conclude, this study positions lysosomal iron as a novel therapeutic lever to target resistant solid tumors. Fento-1 operates at the crossroads of redox biology and targeted pharmacology, exploiting an intrinsic metabolic weakness. Translating this concept into the clinic will require identifying ideal targets, therapeutic windows, and the most effective combinations.

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