Ferroptosis, this unique form of apoptosis has become a hot topic in biology and medical research since Prof. Stockwell at Columbia University named it in 2012. As an iron-dependent phospholipid peroxidation-induced apoptosis program, ferroptosis plays a key role in organ damage, degenerative diseases, and susceptibility to drug-resistant cancers.
 

Mechanism of Ferroptosis

The mechanism of ferroptosis involves several key aspects, including the accumulation of ferric ions, lipid peroxidation, imbalance of the antioxidant system, and the role of iron metabolism-related proteins.

First, the accumulation of ferric ions is an important prerequisite for the development of ferroptosis. Intracellular ferric ions transporter proteins, such as Ferroportin and TfR1, as well as FTH1, are involved in the absorption, transport, and storage of ferric ions. Abnormal function or changes in the expression of these proteins can lead to elevated levels of intracellular ferric ions, thus providing a material basis for the development of ferroptosis.

Secondly, the lipid peroxidation reaction is a direct trigger of ferroptosis. Polyunsaturated fatty acids in the cell membrane are the main substrates for lipid peroxidation, and ferric ions act as catalysts to promote the lipid peroxidation reaction. Free radicals such as superoxide anion (O2^-) and hydroxyl radical (OH^-) are generated in the presence of ferrous ions, which further trigger lipid peroxidation and the formation of lipid peroxides (e.g., malondialdehyde, MDA). These peroxides are not only capable of destroying the integrity of cell membranes, but may also lead to organelle dysfunction and even trigger cell death. Intracellular antioxidant systems, such as glutathione peroxidase (GPX4) and thioredoxin (Trx), are responsible for scavenging these free radicals and peroxides. When the function of the antioxidant system is impaired or ferric ions accumulate in excess, lipid peroxidation is exacerbated, ultimately leading to ferroptosis.

In addition, iron metabolism-related proteins play a key role in the regulation of ferroptosis. For example, Ferroptosis suppressor (FSP1) prevents ferroptosis by reducing lipid peroxides. Glutathione peroxidase 4 (GPX4), one of the most important inhibitors of ferroptosis, scavenges lipid peroxides and maintains the balance of the intracellular antioxidant system. In addition, regulators of iron metabolism, such as Hepcidin and Iron Regulatory Protein (IRP), indirectly influence the development of ferroptosis by regulating the absorption, transport and storage of ferric ions.
 

Ferroptosis Research Direction

Ferroptosis, as a novel mode of programmed cell death, is gradually revealing its important role in disease research. Currently, the research on ferroptosis focuses on the following aspects:

1. Mechanism and regulation: To study the molecular mechanism and regulatory network of Ferroptosis, including key processes such as ferric ion metabolism, oxidative stress, lipid peroxidation, etc., and to reveal the signaling pathways and regulatory mechanisms of Ferroptosis. To establish and apply appropriate cellular and animal models to study the biological process of Ferroptosis, and to deeply understand the physiological and pathological significance of Ferroptosis.
2. Disease association: to explore the association of Ferroptosis with a variety of diseases, such as tumors, neurological diseases, cardiovascular diseases, etc., and to reveal the role of Ferroptosis in the occurrence, development, and treatment of these diseases, in order to search for new therapeutic strategies and targets.
3. Antioxidant and drug screening: Screening and evaluating compounds, natural products, etc. to find molecules with anti-ferroptosis activity to discover new antioxidants and drugs for ferroptosis intervention and treatment.

 

Ferroptosis and Disease: Inextricably Linked

Ferroptosis has shown remarkable potential in many fields, especially associated with diseases. From the dilemma of tumor treatment, to the exploration of neurodegenerative diseases, to the deciphering of ischemia-reperfusion injury, ferroptosis is like a key clue hidden behind the disease, linking up the various links of pathophysiological changes.

①A new dawn in the field of tumor
Tumor cells are known for their ability to proliferate and survive, and traditional therapies often face the problems of drug resistance and recurrence. The discovery of ferroptosis has brought a new opportunity for tumor treatment. Studies have shown that many tumor cells are more sensitive to ferroptosis than normal cells. This is because tumor cells are in a high metabolic and oxygen-rich environment, which itself is accompanied by a certain degree of oxidative stress, and there are specific changes in their iron metabolism and antioxidant defense system. Scientists are trying to break through the bottleneck of traditional treatment by inducing ferroptosis in tumor cells. For example, in some refractory tumor models, the use of ferroptosis-inducing agents can specifically kill tumor cells, inhibit tumor growth, and show synergistic effects when applied in combination with chemotherapy and radiotherapy, thus lighting up the light of hope for the attack of cancer.

②Potential keys to neurodegenerative diseases
Neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease have long plagued medical researchers. Progressive neuronal death is a central pathological feature of these diseases, and in-depth studies of the ferroptosis mechanism have provided new clues to explain the cause of neuronal death. Abnormal deposition of ferric ions, increased lipid peroxidation, and altered activity of antioxidant enzymes in diseased brain regions are often accompanied by ferroptosis, and these phenomena are highly consistent with the occurrence of ferroptosis. Further studies have revealed that inhibition of ferroptosis-related pathways can reduce neuronal damage and slow down the disease process to a certain extent, which undoubtedly opens up a completely new direction for the development of therapeutic drugs for neurodegenerative diseases.

③Double-edged sword in ischemia-reperfusion injury
In cardiovascular and organ transplantation fields, ischemia-reperfusion injury is a critical issue that needs to be addressed. When blood perfusion is restored after transient ischemia in tissues and organs, instead, strong oxidative stress and cell death are triggered, aggravating tissue injury. Ferroptosis is involved in this process. On the one hand, the imbalance of intracellular iron homeostasis and the initiation of lipid peroxidation in the ischemic and hypoxic environment set the stage for ferroptosis after reperfusion; on the other hand, the moderate activation of the ferroptosis pathway removes severely damaged and unrepairable cells, which may create favorable conditions for tissue repair and regeneration. How to precisely regulate the “switch” of ferroptosis in ischemia-reperfusion injury to minimize the damage and maximize the repair has become one of the hotspots in current research.
 

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Reference (the literature)

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