Background
Ferroptosis is a novel regulated cell death (RCD) mode caused by damage to lipid membranes due to the accumulation of lipid peroxides and reactive oxygen species (ROS) produced by iron metabolism, which was first observed and named by Stockwell in 2012 [
1,
2]. Ferroptosis is driven by lethal lipid peroxidation resulting from imbalances in cellular metabolism and redox homeostasis [
2]. More and more studies have shown that ferroptosis is involved in stress processes such as endoplasmic reticulum stress and autophagy, and ferroptosis is associated with many diseases, including degenerative diseases, cancer, acute kidney injury, I/R injury of the heart, liver, and kidney, as well as other diseases such as acute myeloid leukemia, age-related macular degeneration (AMD), psoriasis, and hemolytic disorders [
1,
3]. Induction of ferroptosis by experimental small-molecule compounds or clinical drugs is emerging as an effective antitumor strategy for various types of cancer, especially in iron-rich and higher mitochondrial abundance tissues such as hepatocellular carcinoma (HCC), pancreatic ductal adenocarcinoma (PDAC), breast cancer and non-small cell lung carcinoma (NSCLC) [
4,
5]. Here we summarize the role of ferroptosis in cellular stress responses, as well as its potential role in cancer radiotherapy and immunotherapy.
Conclusions and perspectives
As a novel iron-dependent non-apoptotic RCD, ferroptosis has attracted extensive attention since its discovery. Ferroptosis is deeply involved in the regulation of cellular stress processes such as ER stress and autophagy, and affects the occurrence and development of cancer through a complex and sophisticated signal transduction network. Currently, targeting ferroptosis is emerging as a potentially effective approach for the treatment of various diseases, especially cancer and ischemic organ damage. Fortunately, available evidence suggests that ferroptosis and other known types of RCDs do not appear to be antagonistic to each other, but may coexist and interfere with each other, and act synergistically in cell fate determination. Therefore, the induction of mixed RCD can undoubtedly be an effective therapeutic strategy to break the bottleneck of the limitations of radiotherapy alone. In addition, the reciprocal regulatory feedback between ferroptosis and immune responses may further exert tumor suppressive effects. Furthermore, targeting ferroptosis using small molecule compounds, clinical drugs, and nanoparticles is also a potentially effective antitumor strategy in clinical practice, especially in iron-rich tumors that are prone to ferroptosis.
However, the existing understanding of ferroptosis remains insufficient. First, the execution mechanism of ferroptosis is still unclear. Lethal plasma membrane damage due to lipid peroxidation is the direct cause of ferroptosis; however, whether other unknown downstream molecules exist to directly regulate and execute ferroptosis, like a role BCL family proteins or Caspase-3 served for apoptosis, is still elusive. Therefore, cracking the execution mechanism of ferroptosis remains one of the critical issues in the next few years.
Second, the selective mechanism of ferroptosis remains poorly understood. At present, it is still at a loss when mentioned to selectively activate or inhibit ferroptosis in specific tissues and cells in different diseases. Whether pharmacological intervention can selectively inhibit tumor cells without causing severe toxic side effects on normal cells remains to be verified. Comprehensively understanding the susceptibility mechanism of cancer cells and immune cells to ferroptosis, selectively inhibiting or promoting ferroptosis of immune cells, and creating an antitumor immune microenvironment are still important issues to be solved urgently.
Third, definitive biomarkers for ferroptosis have not been identified. The search for predictive clinical biomarkers of ferroptosis, especially those that can be directly and rapidly detected in patient body fluids and biopsy samples, will be of fundamental importance in determining the physiological function and therapeutic potential of ferroptosis. Thus, finding biomarkers to facilitate the accurate detection of ferroptosis will also be an active area of research in the coming years.
Fourth, the clinical translation potential of targeted ferroptosis therapy needs to be validated. Based on the results obtained so far, approaches that combine FINs with other therapies, such as radiotherapy and immunotherapy, to improve the treatment effect have great potential for clinical translation. Unfortunately, most FINs exhibit poor pharmacology and pharmacokinetics in animal models, which directly limits their clinical application. Existing medicines, such as Sorafenib, Lapatinib, Sulfasalazine, Cisplatin, etc., can effectively induce ferroptosis [
79,
201‐
203]. However, a recent study showed that sorafenib is not qualified as an effective ferroptosis inducer, and ferroptosis induced by system Xc
− inhibitor can only be achieved in a subset of tumor cell lines [
204]. Thus, under the premise of rigorous evaluation, innovative uses of these medicines in combination with other therapies to target ferroptosis may acquire great potential in specific types of tumor therapy. In addition, nanoparticles coated with specific ligands and carrying targeted drugs also have good potential for clinical translation. However, the stability, targeting capabilities, kinetics, and toxicity of nanocarriers still need to be intensively studied in vivo.
Addressing these unanswered questions promises to yield new insights, not only for ferroptosis research itself, but also for the biomedical frontiers associated with this novel RCD. It is believed that in the next few years, there will be exciting discoveries in the field of ferroptosis-related research. Based on specific biomarkers and precise patient-specific assessment, targeting ferroptosis will be translated into a practical new approach to clinical cancer therapy, significantly contributing to the prevention, diagnosis, prognosis, and treatment of cancer.
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