Recent advancements in cancer research are shedding light on a novel therapeutic strategy aimed at overcoming the formidable challenge of cancer stem cells (CSCs). These unique cells are known for their remarkable ability to resist conventional therapies, leading to treatment failures and cancer recurrence. A promising new approach involves targeting ferroptosis, a regulated cell death process driven by iron accumulation and lipid peroxidation, which could significantly improve cancer treatment outcomes.

CSCs are notorious for their ability to evade standard treatments, primarily due to their resilience to oxidative stress and enhanced iron uptake. Unlike typical cancer cells, CSCs maintain low levels of reactive oxygen species (ROS), allowing them to survive under hostile conditions within the tumor microenvironment. Traditional therapies that aim to eliminate rapidly dividing cancer cells often fall short against these dormant, therapy-resistant CSCs. However, targeting ferroptosis represents a strategic pivot that could potentially disrupt the survival mechanisms of CSCs.

Ferroptosis is fundamentally different from other forms of cell death, such as apoptosis and necrosis, as it is primarily driven by iron-dependent lipid peroxidation. Key regulatory pathways, including the cystine/glutathione axis, significantly influence CSCs' vulnerability to ferroptosis. The regulation of iron metabolism within CSCs is pivotal, as these cells exhibit increased iron intake compared to non-stem cancer cells. This difference in iron homeostasis makes CSCs particularly susceptible to treatments that induce ferroptosis, opening new avenues for selective cancer cell elimination.

Pharmacological approaches to induce ferroptosis include the inhibition of SLC7A11, a transporter that controls cysteine availability. Reducing cysteine disrupts glutathione synthesis, making CSCs more vulnerable to oxidative damage. Additionally, manipulating iron metabolism or enhancing lipid peroxidation can selectively induce cell death in CSCs without significantly affecting normal cells. Innovations such as nanoparticle drug delivery systems are proving effective in increasing intracellular iron and ROS levels specifically within CSCs.

The potential of targeting ferroptosis in CSCs lies not only in reducing cancer recurrence but also in overcoming resistance to existing therapies. As the understanding of the complex interplay between ferroptosis and CSC biology deepens, there is optimism for developing personalized cancer treatments that are both more effective and less prone to resistance. Further research is essential to optimize these strategies and fully harness the therapeutic potential of ferroptosis in combating cancer.
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Reference
Luyao Wang, Ye Zhu, Chengying Huang, Qiuming Pan, Junxi Wang, Hongrui Li, Yudi Huang, Guozhong Yi, Zhiyong Li, Songtao Qi, Guanglong Huang, Shanqiang Qu, Targeting ferroptosis in cancer stem cells: A novel strategy to improve cancer treatment, Genes & Diseases, Volume 12, Issue 6, 2025, 101678, https://doi.org/10.1016/j.gendis.2025.101678

Funding Information:
President Foundation of Nanfang Hospital, Southern Medical University (China) 2022A018
Science and Technology Projects in Guangzhou, China 2024A04J5111
GuangDong Basic and Applied Basic Research Foundation (China) 2023A15111129