• Ferroptosis as a therapeutic strategy in cancer
  • Yasaman Baharvand,1 Maryam Naderi Soorki,2,* Mozhdeh Hosseini,3
    1. Department of Biology, Faculty of Sciences, Shahid Chamran University of Ahvaz, Ahvaz, Iran
    2. Department of Biology, Faculty of Sciences, Shahid Chamran University of Ahvaz, Ahvaz, Iran
    3. Department of Biology, Faculty of Sciences, Shahid Chamran University of Ahvaz, Ahvaz, Iran


  • Introduction: Cancer remains one of the most serious threats to human health. Although a variety of treatment approaches are available and modern medicine has advanced greatly, cancer therapy still struggles with the challenge of selectively destroying cancer cells while sparing normal cells, in order to reduce treatment-related toxicity. Targeting regulated cell death (RCD) has become a central focus in cancer research (1). Ferroptosis is a recently identified, iron-dependent form of programmed cell death and unlike apoptosis, necrosis, or autophagy, ferroptosis is characterized by glutathione (GSH) depletion, reduced activity of glutathione peroxidase 4 (GPX4), and the inability of GPX4 to metabolize lipid peroxides. In addition, Fe²⁺-mediated lipid oxidation generates reactive oxygen species (ROS), which drive the induction of ferroptosis (2). Ferroptosis is characterized by lipid peroxidation which is mainly regulated by GPX4. This enzyme suppresses ferroptosis by blocking iron-dependent lipid reactive oxygen formation, achieved through catalyzing the reduction of R-OOH to R-OH. (3). It is well established that cancer cells can evade and resist classical cell death pathways such as apoptosis. This resistance contributes to invasion, metastasis, and therapeutic failure. Ferroptosis is as a newly identified form of cell death that provides a promising strategy to eliminate cancer cells that are resistant to conventional treatments (4). Mesenchymal and dedifferentiated cancer cells which are resistant to apoptosis and traditional therapies show high sensitivity to ferroptosis (6). This vulnerability offers a new therapeutic strategy. The altered metabolism, elevated ROS, and genetic mutations in cancers such as clear cell renal cell carcinoma pancreatic ductal adenocarcinoma, and triple-negative breast cancer make them prone to ferroptosis. Mesenchymal-like cancer cells resist many therapies but they remain sensitive to ferroptosis inducers (2). In this review, we focus on the potential of ferroptosis as a promising strategy for cancer treatment.
  • Methods: We conducted a literature search in trusted scientific databases, including PubMed, Scopus and google scholar. Our focus was on studies related to ferroptosis and cancer therapy. Only peer-reviewed articles and reliable reviews were included for analysis.
  • Results: Recently, Ferroptosis has been recognized as an important mechanism in anticancer therapy (7). Therapies that induce ferroptosis have therefore become a promising approach in oncology (2). A notable breakthrough was the discovery that cells with acquired resistance to the human epidermal growth factor receptor (HER1/HER2) tyrosine kinase inhibitor Lapatinib were selectively sensitized to ferroptosis. This was the first evidence that cancer cells escaping other treatment modalities could remain vulnerable to ferroptotic death. More recently, immunotherapy has also been shown to enhance tumor cell sensitivity to ferroptosis (8). In 2014, Yang and colleagues reported that renal cell carcinoma is highly susceptible to ferroptosis and identified GPX4 as a key regulator of this process. GPX4 catalyzes the reduction of lipid peroxides, providing essential protection against excessive lipid peroxidation. A year later, in 2015, Jiang and colleagues discovered that suppression of the p53 tumor suppressor pathway which is commonly inactivated in many human cancers, was also linked to ferroptosis resistance. They showed that activation of p53 reduced cystine uptake via the cystine/glutamate antiporter, which limited the intracellular production of GSH and in turn protected tumor cells from undergoing ferroptosis. Further evidence was provided by Alvarez and colleagues, who demonstrated that resistance to ferroptosis is essential for lung adenocarcinoma survival in oxygen-rich environments (7). In pancreatic ductal adenocarcinomas, SLC7A11 is overexpressed which leads to increased cystine uptake and GSH synthesis and these changes support cancer cell growth and survival by suppressing ferroptosis. In these cells, HSPA5 (heat shock 70 kDa protein 5) functions as a negative regulator of ferroptosis, and its silencing enhances erastin-induced cell death in a ferroptosis-dependent fashion. ATF4 promotes the expression of HSPA5, which subsequently interacts with GPX4, resulting in the inhibition of ferroptosis. The ATF4-HSPA5-GPX4 axis reduces the anticancer efficacy of gemcitabine through its role in ferroptosis regulation (9).
  • Conclusion: Ferroptosis is a form of cell death that depends on iron and ROS, and it opens up new possibilities for cancer treatment. Because it works differently from traditional cell death pathways, it may help overcome drug resistance and make therapies more effective. By learning how ferroptosis works and finding ways to target it, we could develop better strategies to slow tumor growth and improve outcomes for patient.
  • Keywords: Ferroptosis, Regulated cell death, Cancer therapy, Drug resistance