June 25, 2024

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Nature: The Pathogenesis Biology and Role of iron death in diseases

Nature: The pathogenesis, biology and role of iron death in diseases


Nature Review:  The Pathogenesis Biology and Role of iron death in diseases

Since the term iron death was proposed in 2012, iron death has attracted much attention. This unique cell death program is driven by iron-dependent phospholipid peroxidation and is regulated by multiple cellular metabolic pathways (including redox homeostasis, iron metabolism, mitochondrial activity, and amino acid, lipid and sugar metabolism), and Various signal pathways related to diseases.


Most organ damage and degenerative diseases are caused by iron death. Drug-resistant tumor cells, especially those in the mesenchymal state and easily metastasized, are very prone to iron death.

Therefore, the induction and inhibition of iron death through pharmacological regulation has great potential in the treatment of drug-resistant tumors, ischemic organ damage and other degenerative diseases related to extensive lipid peroxidation.

In 2021, a review titled “Ferroptosis: mechanisms, biology and role in disease” on “NATURE REVIEWS | MOLECULAR CELL BIOLOGY”, systematically expounding the molecular mechanism and regulatory network of iron death, and iron death is inhibiting The physiological functions, pathological effects, and potential of targeted therapy in tumor and immune monitoring; some important concepts and urgent problems to be solved are discussed. These are the focus of future iron death research. The brief introduction is as follows:

Nature: The pathogenesis, biology and role of iron death in diseases



Among the factors that cause cell oxidative stress, the lipid oxidative modification in the lipid bilayer —especially lipid peroxidation—has become an important regulator that determines the fate of cells. A wide range of lipid peroxidation Cell death occurs in a way called iron death.

Lipid peroxidation is affected by the combination of environment and genes, including heat, radiation, metabolism, redox homeostasis and cell-to-cell contact, as well as carcinogenic and tumor suppressor signals. Like the factors that induce iron death, more and more evidence shows that iron death plays a potential physiological role in tumor suppression and immunity (Figure 1).

At the same time, iron death also affects the development of certain fungi and the senescence of nematodes. Studies have clarified the pathophysiological relationship of iron death, which is particularly significant in treating tumors and preventing organ ischemic damage (Figure 1).

Nature: The pathogenesis, biology and role of iron death in diseases


Harry Eagle observed this iron-like death phenomenon from 1950 to 1960. Lack of cysteine ​​can lead to cell death, and endogenous synthetic cysteine ​​can resist cell death. Cysteine ​​is the rate-limiting factor in reducing glutathione (GSH) biosynthesis.

For glutathione synthesis, cysteine ​​can pass through neutral amino acid transporters or throughThe X- c –Cystine/glutamate reverse transporter (transmembrane protein complex containing SLC7A11 and SLC3A2 subunits, hereinafter referred to asThe X- c -System) is oxidized and taken up from the environment or synthesized by the transsulfurization pathway of methionine and glucose.

Existing studies show that GSH synthesis or enhanced X- C – system or activity GPX4 can make a variety of cells from oxidative stress, especially in the absence of cell death caused by thiol, these early studies iron death mechanisms.



The mechanism of iron death

Early studies suggest that X- C – System -GSH-GPX4 death pathway inhibition of iron, and phospholipid hydroperoxide (PLOOHs) is a lipid based on active oxygen (ROS) form, is the key iron death (FIG. 2) is suppressed.

The iron death monitoring pathway that relies on GPX4 has been found, and the mechanism of PLOOH synthesis, especially the synthesis and activation of the precursor polyunsaturated fatty acids (PUFAs) of PLOOHs, has also attracted much attention.

These studies have focused on cell metabolism, revealing the close connection between iron death and metabolic pathways. GPX4 is the main PLOOH neutralizing enzyme, and a mainstream mechanism is that erastin/RSL3 induces iron death.

This mechanism indicates that the inactivation of GPX4-RSL3 directly induces iron death, and erastin inhibits the transfer of cystine to make cells lose cysteine, and cysteine ​​is a basic cell component of GSH, which indirectly induces iron death.

The accumulation of PLOOHs can cause rapid and irreparable damage to the cell membrane, leading to cell death (Figure 2a). Therefore, these studies define iron death as a cell death process, and its mechanism is different from other known death processes.


Nature: The pathogenesis, biology and role of iron death in diseases



Drivers of phospholipid peroxidation

Unrestricted lipid peroxidation is characteristic of iron death. Early studies in 1950 showed that the trace elements selenium, vitamin E and cysteine ​​may inhibit lipid peroxidation.

The activation of lipid peroxidation requires the removal of a bisallyl hydrogen atom (located between two carbon-carbon double bonds) from the phospholipids (PUFA-PLs) containing polyunsaturated fatty acyl groups in the lipid bilayer. Then a carbon-centered phospholipid group (PL•) is formed, which then reacts with oxygen to produce a phospholipid hydrogen peroxide radical (PLOO•), and removes a hydrogen from another PUFA to form PLOOH (Figure 3).

If GPX4, PLOOH and lipid free radicals (especially PLOO• and alkoxy phospholipid free radicals (PLO•)) are not converted into corresponding alcohols (PLOH), these substances will be removed by removing PUFA-PLs at the distal end. Hydrogen atoms react to produce PLOOH, and react with oxygen molecules to produce PLOOHs (Figure 3).

Ultimately, this will produce many products, including the breakdown products of lipid peroxides (such as 4-hydroxynonenoic acid and malondialdehyde) and oxidized and modified proteins.

This chain reaction may eventually destroy the integrity of cell membranes and cause organelles and/or cell membranes to rupture. In neuron-related studies, it has been shown that membranes with higher PUFA-PL content are susceptible to peroxidation. Existing research is still unclear what kind of lipid peroxidation cell membranes (such as mitochondria, endoplasmic reticulum, peroxisomes, lysosomes and plasma membranes) are related to iron death.

The sensitivity of cells to iron death depends on the degree of unsaturation of the lipid bilayer, but how lipid peroxidation occurs is still unclear. The production of lipid radicals or hydroxyl radicals (•OH) can trigger non-enzymatic lipid peroxidation reactions, which may be driven by the Fenton reaction with iron as a catalyst (Figure 3).

Certain lipoxygenases (LOXs) are non-dependent heme dioxygenases targeting PUFAs, which can directly oxidize PUFAs and PUFA-containing lipids on biofilms, indicating that LOXs may be able to induce iron death. The role of LOXs in iron death is unclear, and the latest research shows that the pan-expressed cytochrome P450 oxidoreductase (POR) also plays a role in lipid peroxidation.

NADPH provides electrons through POR, and the downstream electron acceptors (such as cytochrome P450 and CYB5A) accept electrons and decrease accordingly. This may be due to the dehydrogenation of PUFAs or the reduction of trivalent iron ( F e3 + ) is converted to divalent iron ( F e 2+ ) (Figure 3) directly or indirectly triggers lipid peroxidation.

Below, F. E . 3 + and F. E 2+ circulated between the Fenton reaction is essential for and lipid peroxidation.

Nature: The pathogenesis, biology and role of iron death in diseases




Metabolism of iron death

The role of iron, lipids, ROS and cysteine ​​in iron death indicates that there is a close connection between the mode of cell death and cell metabolism. Jiang’s research attempts to explore how metabolism determines the fate of cells to further reveal the complex relationship between iron death and metabolism.

The catabolic process of autophagy is an important survival mechanism in response to various stresses, but whether autophagy can promote cell death (ie “autophagic cell death”) and how to promote cell death has been debated for decades.

Studies have found that when the culture medium has complete serum and lacks amino acids (a state that triggers autophagy), autophagy promotes non-apoptotic, non-necrotic cell death.

The transferrin and glutamine in the serum are necessary for this form of cell death, and specifically depriving the cell culture medium of cysteine ​​can trigger cell death. The protective effects of dependence on iron and cysteine ​​indicate that iron death is a mechanism of cell death under these conditions.

Autophagy in the iron death caused by lack of cysteine ​​is achieved by autophagy degradation of ferritin (also called iron autophagy protein), which increases the unstable iron content in the cell and makes iron death more sensitive (Figure 4).

Glutamine metabolism or glutamine breakdown is necessary for iron death due to lack of cysteine, which links iron death to oxidative metabolism.

Glutamine is a key replenishing metabolite that promotes the mitochondrial tricarboxylic acid cycle (TCA), which increases the respiration rate of the mitochondria and promotes the production of ROS.

Therefore, the normal metabolic function of mitochondria is related to iron death-this conclusion has been confirmed by pharmacological, cytological and genetic analysis (Figure 4).



Monitoring channels not relied on GPX4

Recently, a genome-wide screening revealed an iron death monitoring mechanism that does not rely on GPX4. The first mechanism involves iron death suppressor protein 1 (FSP1; also known as AIFM2). AIFM1 was originally considered to be a homolog of FSP1, which can promote cell apoptosis (such as FSP1/AIFM2).

It is now believed to be related to the transport and correct folding of proteins between mitochondrial membranes. FSP1 lacks substantial pro-apoptotic function, but can actually protect cells from iron death caused by inhibition or lack of GPX4 gene.

FSP1 is myristoylated and is related to a variety of cell membrane structures (including cell membranes, Golgi apparatus, and perinuclear structures). Mutations in the myristoylation site will lose the anti-iron death function.

Due to the ubiquinone oxidoreductase activity of NADH, FSP1 reduces lipid peroxidation and iron death by reducing ubiquinone (or its partial oxidation product semi-hydroquinone) to produce ubiquinol to inhibit lipid peroxidation and iron death, thereby directly reducing lipid free radicals and terminating lipids Auto-oxidation or indirectly stops lipid auto-oxidation by regenerating and oxidizing vitamin E (a powerful natural antioxidant) (Figure 2b). Another study showed that GTP cyclohydrolase 1 (GCH1) prevents iron death through its metabolites tetrahydrobiopterophyllin ( BH 4 ) and dihydrobiopterocarcinoma ( BH 2 ).

BH 4 has anti-oxidative degradation effects on phospholipids containing two PUFA tails, which may involve a dual mechanism: directly capture antioxidant free radicals and participate in the synthesis of ubiquinone (Figure 2c).

Although the role of GCH1 in protecting tissues and organs from iron death is still unclear, gene knockout studies have shown that mice lacking the GCH1 gene will develop bradycardia and embryonic death in the second trimester.

In addition to peroxides that act directly on the lipid bilayer or free radicals that act on phospholipids by capturing antioxidant free radicals, there may be other mechanisms that can protect cells from lipid peroxidation damage.

Squalene is a metabolite of cholesterol metabolism. It has anti-iron death effects in cholesterol-deficient lymphoma cell lines and primary tumors. However, whether this is a tumor subtype-specific effect or a common protective mechanism remains to be verified (Figure 2c) ).


Hippo–YAP signaling pathway in iron death

The Hippo-YAP signaling pathway is involved in a variety of biological functions, including the control of cell proliferation and organ size. Researchers have studied the role of this pathway in iron death and observed that high-density cells tend to be more resistant to iron death induced by lack of cysteine ​​and inhibition of GPX4.

In terms of mechanism, the cell density effect of iron death in epithelial cells is mediated by E-cadherin-mediated cell-cell contact, which activates the Hippo signaling pathway through NF2 (also known as Merlin) tumor suppressor protein. Thus inhibiting nuclear translocation and transcription co-regulate the activity of YAP factor.

YAP targets several regulators of iron death (ACSL4, transferrin receptor and other regulators), and the susceptibility to iron death depends on the activity of the Hippo pathway, which increases with the inhibition of Hippo and activation of YAP ( Figure 4).

The YAP analogue TAZ was found to promote iron death through cell density regulation in kidney cancer cells that mainly express TAZ instead of YAP. The E-cadherin–NF2–Hippo–YAP/TAZ pathway plays an important role in determining the sensitivity to iron death.

First of all, multiple components of this pathway are frequently mutated in tumors, which can enhance YAP/TAZ expression and/or activity, and induction of iron death may become a potential treatment for certain specific tumors. Secondly, cell density-dependent iron death has also been observed in non-epithelial cells that do not express E-cadherin.

Researchers believe that other cadherins or cell adhesion molecules may also inhibit iron death through similar mechanisms. Thirdly, the Hippo-YAP pathway is very important during development.

It interacts with a variety of signaling pathways, and there may be a connection between iron death and normal cell biology. Finally, the researchers speculated that the original function of cadherin might be to protect cells from oxidative stress and iron death.



AMPK signaling pathway in iron death

Cell metabolic stress and lack of glucose increase the production of ROS, indicating that lack of glucose promotes iron death. However, some studies believe that lack of glucose can inhibit iron death. This protection depends on the activity of adenylate-activated protein kinase (AMPK). In the absence of glucose, AMPK is activated and the energy stress protection program is activated to combat iron death by disrupting the biosynthesis of PUFAs, which are essential for iron death driven by lipid peroxidation (Figure 4).



Iron death in tumor suppression

Studies have shown that a variety of tumor suppressor factors can make cells sensitive to iron death. Careful analysis of p53-specific lysine acetylation sites, the researchers found that p53 by inhibiting the X- c – to enhance iron death subunit transcription SLC7A11 system, which may be involved in p53 in vivo and in vitro tumor suppressor function.

Tumor-susceptible p53 single nucleotide polymorphism caused the substitution of P47S amino acids, which resisted tumor cell iron death.

It is not clear whether the loss of iron death activity by p53 is the only functional consequence of these specific mutations. In contrast, p53 also prevents iron death by regulating other transcription targets. Since p53 regulates target genes involved in a variety of biological processes, its exact role in iron death may be related to the environment.

Similar to p53, tumor suppressor and epigenetic regulator BAP1 promote iron death by down-regulating the expression of SLC7A11. Different from p53, P53’s iron death-promoting activity has been proven to inhibit the occurrence of tumors in the body, but it is not clear whether BAP1’s iron-death activity can produce tumor suppressor function.



Iron death in immune surveillance

Studies have shown that iron death plays an important role in cell death induced by immune cells. IFN -γ (IFNγ) to suppress X- C – expression systems, CD8 + T cells produce cytokines iron sensitizing tumor cells death.

Whether the mechanism by which immune cells induce iron death is related to their physiological functions remains unclear. IL-4 and IL-13 inhibit the expression of GPX4 and increase the expression of ALOX15 in certain cells (kidney, lung, spleen and heart), and produce a large number of important inflammatory intermediates-arachidonic acid metabolites.

GPX4 inhibits the activity of LOXs and cyclooxygenase by reducing lipid peroxidation, impairing the activity of GPX4, which may affect the secretion of immunoregulatory lipid mediators, and then inform the immune system cells to be in a state of iron death sensitivity, which is helpful for immune monitoring ( Discovery of injury or malignant tumor).



Potential anticancer therapy to induce iron death

Currently, cancer treatment methods based on induced iron death are actively sought. Attempts have been made to use nanoparticle-based non-targeting strategies to deliver iron, peroxides and other toxic substances to kill tumor cells. The existence of a variety of enzymes that regulate iron death has allowed the development of targeted therapy.

The most significant target is GPX4, which is expressed in most cancer cell lines and is important for the survival of cancer cells. The lack of the classic small molecule binding pocket of GPX4 and the existing GPX4 inhibitors covalently modify the selenocysteine ​​residues of GPX4 and other selenoproteins with specificity and potential toxicity.

These inhibitors are highly active and unstable, but they can be overcome by the development of encapsulated prodrugs, which are metabolized in cells to convert them into active forms. GPX4 is essential for various peripheral tissues, such as renal tubular cells and certain neuronal subpopulations in mice.

Therefore, unless treatments that target tumor cells are used, targeting GPX4 may have side effects. GPX4 targeting different, taking into account the knock-out gene Slc7a11 mice without causing major pathological changes and the expression of SLC3A2 and / or Slc7a11 genes negatively correlated with clinical outcome in patients with melanoma and glioma, by inhibiting the X- C – system The method of limiting cellular cysteine ​​is very promising.

Indeed, in mice or by pharmacological inhibition Genetics X- C – to inhibit growth and metastasis of various tumors have been very promising results of the system, it is both effective and low toxicity.

Inhibition of tumor tissue than normal X- C – system because it is more likely susceptible active metabolic changes and other aspects, for a duration of oxidative stress, and therefore more dependent on X c – system ROS detoxification function.

Use to suppress the X- c – treatments based systems, the need for tumor patients were stratified clear the X- c -Expression system (e.g., SLC7A11 overexpression of cysteine-dependent cancer cells show clear ROS) and tumor inhibition discussed before deciding X- C – The system is sensitive to other biomarkers.

Similar to the lack of Slc7a11, knocking out Fsp1 will not cause embryo death or produce obvious pathological changes, indicating that targeting Fsp1 has a broad therapeutic window.

FSP1 is abundantly expressed in most cancer cell lines and is the highest-ranked gene among 860 cancer cell lines related to GPX4 inhibitor resistance. GPX4 cancer cells lacking a gene may be a specific FSP iFSP1 inactivate inhibitors, and stored in the synergistic induction of cancer gene GPX4 death by iron and iFSP1 RSL3.

Therefore, FSP1 inhibitors may be used clinically, especially for the treatment of drug-resistant tumors or tumors that exhibit differentiation characteristics.



Expert Comments


As a unique method of cell death, iron death integrates different components of previous cell metabolism into a tight network, including iron, selenium, amino acids, lipids, and redox reactions (Figure 1). With the progress of iron death research, we have begun to realize that this network plays a broad role in biological processes (physiology and pathology).

The definition of iron death is the process by which iron depletion and lipophilic free radical antioxidants (such as iron statin 1, lipoprotein statin 1, vitamin E or ubiquinone) inhibit cell death.

There are two main mechanisms, one is the iron-dependent lethal mechanism, which is not completely equivalent to iron death, and iron death may be related to lysosomal toxicity; the other is the iron-independent oxidative stress mechanism.

The researchers also found another possibility: direct detection of lipid peroxidation (using mass spectrometry, fluorescent dyes or antibodies such as 1F83). The latest research shows that mobilization and up-regulation of transferrin receptors are another potential marker of iron death, which can distinguish the difference between oxidative stress and iron death.

Other iron death markers still have high value in this field. Another focus of the field is that the use of experimental methods is not suitable for dealing with anticipated problems-this is an inevitable problem in any emerging field.

Although considerable progress has been made in the regulatory mechanism of iron death, the exact molecular events of iron death leading to cell death are still unclear. In the next few years, the pathogenesis of iron death is expected to be elucidated.

These studies will in-depth elucidate the physiological and pathological effects of iron death. Under the guidance of the use of specific biomarkers and accurate assessment of the patient’s background, new iron death-based therapies will be discovered and applied in the clinic.






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