Open access peer-reviewed chapter
Ferroptosis in cancer.
Abstract
Ferroptosis, an iron-dependent novel type of cell death, has been characterized as an excessive accumulation of lipid peroxides and reactive oxygen species. A growing number of studies demonstrate that ferroptosis not only plays an important role in the pathogenesis and progression of chronic diseases, but also functions differently in different diseases. As a double-edged sword, activation of ferroptosis could potently inhibit tumor growth and increase sensitivity to chemotherapy and immunotherapy in various cancer settings. Therefore, the development of more efficacious ferroptosis agonists or inhibitors remains the mainstay of ferroptosis-targeting strategy for cancer therapeutics or cardiovascular and cerebrovascular diseases and neurodegenerative diseases therapeutics.
Keywords
- iron metabolism disorder
- ferroptosis
- tumor
- neurodegeneration
- vascular diseases
1. Introduction
Chronic diseases are non-infectious, of long duration, and are persistent diseases. These diseases mainly include cardiovascular and cerebrovascular diseases, tumors, diabetes, and chronic respiratory diseases, etc. According to the statistics of WHO, approximately 41 million people worldwide die of chronic diseases, accounting for 73.6% of all deaths in 2021 [1]. The occurrence and development of chronic diseases are not only complicated in pathological mechanisms, but also affected by many factors such as genetics, understanding of the molecular mechanisms underlying the pathogenesis of chronic diseases is helpful for diagnosis and treatment. In 2012, a new way of cell death, ferroptosis, was discovered and reported, to some extent, the discovery is a milestone in the study of cell death; it provides a new perspective to study the occurrence, development, and prevention of chronic diseases.
As an essential trace element, iron is present in nearly all forms of life and involved in various of biological processes, including respiration, oxygen transport, intermediary metabolism, gene regulation, and nucleotide synthesis and repair [2, 3]. However, dysregulated iron homeostasis leads to common hematological, metabolic, and neurodegenerative diseases.
Ferroptosis is an iron-dependent cell death, it is different from apoptosis, pyroptosis, or necrosis in morphology, genetics, metabolism, and molecular biology [4]. The morphology is mainly manifested as mitochondrial swelling, increased membrane density, smaller volume, decreased number of cristae, increased lamellar phenotype, and increased autophagosomes, etc. Molecular biology is mainly manifested as glutathione (glutathione, GSH) depletion or inactivation of glutathione peroxidases (GPX4), increased intracellular free iron content, and increased production of reactive oxygen species (ROS), etc., ultimately manifested as the accumulation of toxic lipid hydroperoxides in cells [4]. Its main characteristics are excessive accumulation of lipid peroxides and reactive oxygen species [5]. Since the production of toxic lipid hydroperoxides mostly depends on ferrous iron, and specific iron chelators can inhibit iron-disturbance-mediated ferroptosis. Therefore, iron metabolism and lipid peroxidation play an important regulating role in ferroptosis pathways [6, 7], the possible molecular mechanism is shown in Figure 1.
Figure 1.
Molecular mechanism of ferroptosis.
Ferric ions in the circulation are bound to transferrin and transported into the cells through transferrin receptor 1 (TFR1), which is located on the cell membrane. After being reduced to divalent iron in the cell, ferric iron is transported by divalent metal transport1 (DMT1) and released into the cytoplasmic iron pool, excess iron is stored in ferritin. Some studies showed that ferritin selective autophagy promotes ferritin getting into autophagosomes through the nuclear receptor co-activator 4 pathway and results in the releasing of free iron [8].
Generally, it is believed that excess iron causes ferroptosis mainly through reactive oxygen species produced by the Fenton reaction, application of iron chelators can effectively inhibit ferroptosis [10]. Lipid peroxides play the role of agents in the process of ferroptosis, phosphatidyl ethanolamine (PE) is the substrate of choice for lipid oxidation. Therefore, hydrogen peroxide-PE (OOH-PE) is considered to be the main signal of ferroptosis [9]. In the process of lipid peroxidation accumulation, NADPH oxidase, lipoxygenase, Acyl-CoA long-chain family member 4(ACSL4), and lysophosphatidyl cholinyltransferase 3 may play important roles in the occurrence and development of ferroptosis [10, 11, 12]. The commonly used ferroptosis inhibitors ferrostatin-1(Fer-1), liproxstatin-1(Lip-1), and small-molecule compounds such as vitamin E inhibit ferroptosis mainly by scavenging lipid peroxides [13].
Glutathione peroxidase 4 (GPX4) is a crucial enzyme in the regulation of ferroptosis; it catalyzes the reduction of lipid peroxides, converts OOH-PE into OH-PE, further suppressing the occurrence of ferroptosis [14]. Small-molecule compounds such as RSL3 and ML162 can inhibit GPX4 activity, lead to the accumulation of fatty acid free radicals, eventually lead to ferroptosis. Reduced glutathione is coenzyme factor of GPX4, the rate-limiting step in its synthesis is the absorption of cystine [15]. Cystine/glutamate transporter consists of the membrane transporters solute carrier family 7 members of 11 (SLC7A11) and regulatory proteins across the membrane of solute carrier family 3 member 2 (SLC3A2); it can transport cystine into the cell and excrete the same amount of glutamate at the same time [16], serves as an important regulator of ferroptosis. Small molecules such as erastin can inhibit glutamic acid/cystine reverse transporter, causing ferroptosis. Wang lab first reported that gene Slc7a11 knockout can promote the occurrence of ferroptosis in mice [17]. Additionally, a novel ferroptosis inhibiting factor 1 (FSP1) was discovered independently in two labs recently, in their studies, NADPH was used to reduce ubiquinone (CoQ10) to ubiquinol (CoQ10H2), leading to the reduction of lipid peroxidation of cell membranes, thereby inhibiting ferroptosis [18, 19]; these findings provide an important basis of developing drugs targeting ferroptosis.
Although the specific mechanisms of ferroptosis are not fully clarified, with the deepening of the research, researchers gradually found that ferroptosis plays an important role in the development of major chronic diseases [20]. So far, a growing evidence showed that ferroptosis is involved in the pathophysiological process of neurodegenerative diseases, tumors, ischemia–reperfusion injury, kidney injury, and other diseases; recent studies have found that ferroptosis plays an important role in cardiovascular disease. Here, we summarized the latest research progress of ferroptosis in cancer, neurodegenerative diseases, and cerebrovascular diseases, to provide new ideas and strategies for the prevention and treatment of major chronic diseases.
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2. Ferroptosis and tumor
Tumor cells can proliferate by avoiding cell death, and apoptosis, necrosis, autophagy also played important roles in the development of tumor. In Table 1, we summarized the latest research progress of molecular mechanism studies on ferroptosis in common tumors, to provide a series of potential new targets for tumor prevention and control.
| Tumor type | Related studies | Reference |
|---|---|---|
| Hepatocellular carcinoma | Sorafenib induces ferroptosis in hepatocellular carcinoma cells | [21] |
| Retinoblastoma protein-deficient hepatocellular carcinoma cells are more sensitive to sorafenib-induced ferroptosis | [22] | |
| Activation of p62-Keap1-NRF2 leads to ferroptosis resistance in hepatocellular carcinoma cells | [23, 24, 25, 26] | |
| The expression levels of SLC7A11, Rb, and MT1 are related to the prognosis of patients with hepatocellular carcinoma | [22, 27, 28] | |
| Pancreatic cancer | Artesunate induces ferroptosis in pancreatic ductal adenocarcinoma cells | [29, 30] |
| Piperamide induces ferroptosis in pancreatic ductal adenocarcinoma cells | [31] | |
| Combination of piperamide, Cotylenin A, and sulfasalazine effectively inhibits pancreatic cancer via ferroptosis | [31] | |
| Renal cell carcinoma | Compared with other tumor cells, renal clear cell carcinoma cells are more sensitive to ferroptosis induced by glutathione peroxidase 4 inhibition | [32] |
| HIF-2α-HILPDA pathway regulates the sensitivity of renal clear cell carcinoma cells to ferroptosis | [33] | |
| TAZ/EMP1/NOX4 pathway regulates the sensitivity of renal clear cell carcinoma cells to ferroptosis | [34, 35] | |
| Breast cancer | Siramesine combined with apatinib upregulates iron levels and induces ferroptosis in breast cancer cells | [36] |
| Mucin 1C subunit, SLC7A11, and CD44v form a complex to upregulate reduced glutathione expression and make triple-negative breast cancer cells resistant to ferroptosis | [37] | |
| Sulfasalazine inhibits the growth of glutamine auxotrophic triple-negative breast cancer cells | [38] | |
| SLC7A11 is closely related to drug resistance and metastasis of triple-negative breast cancer cells | [39] | |
| Transferrin receptor expression level is associated with breast cancer prognosis | [40, 41] | |
| Bladder tumor | Ferritin phagocytosis releases intracellular free iron and induces ferroptosis and inhibits bladder tumors. | [44] |
Table 1.
SLC7A11: solute carrier family 7 member 11; Rb: retinoblastoma; MT1: metallothionein 1.
2.1 Ferroptosis and hepatocellular carcinoma (HCC)
Targeting ferroptosis is a potential mechanism in the treatment of hepatocellular carcinoma (HCC) [21]. Retinoblastoma (Rb)-deficient cancer cells are more sensitive to ferroptosis induced by sorafenib [22], it is likely that it enhances the oxidative stress response by affecting the concentration of reactive oxygen species in mitochondria. Furthermore, Sun et al. found that nuclear factor E2–related factor 2 (NRF2) protects hepatocellular cancer cells from ferroptosis induced with sorafenib, indicating that targeting p62-Keapl-NRF2 pathway may overcome sorafenib resistance in hepatocellular carcinoma cells [23, 24, 25, 26]. Additionally, NRF2 also induces expression of metallothionein1G (MT-1G), an important negative regulator of ferroptosis, through the cythionase pathway, leading to sorafenib resistance in cancer cells [27]. CDGSH [Fe-S]-containing domain 1 can protect the mitochondria from ferroptosis in hepatocellular cancer cells and can be upregulated by erastin in an iron-dependent manner [28]. Moreover, p53S47 mutation carried by hepatocellular carcinomas causes ferroptosis tolerance by inhibiting ASCL4 [28].
In hepatocellular carcinoma, the expression of ferroptosis-related genes is related to the prognosis of patients, the mRNA expression levels of
2.2 Ferroptosis and pancreatic cancer
The main mechanism of pancreatic cancer is that mutated KRAS gene reprograms pancreatic ductal adenocarcinoma (PDAC) cells to a state that is highly resistant to apoptosis. Artesunate can induce tumor cell apoptosis by generating reactive oxygen species [30]. Eling et al. found that artesunate can induce ferroptosis in PDAC cells with KRAS mutations and the process can be effectively inhibited by Fer-1 [31]. Yamaguchi et al. found that the natural product piperamide can induce ferroptosis in tumor cells by promoting the generation of reactive oxygen species, and its anti-tumor effect can be inhibited by antioxidants, ferroptosis inhibitors, and iron chelators [32]. The combined use of piperamide, Cotylenin A (a plant growth regulator), and sulfasalazine has a good synergistic effect on pancreatic cancer. These results suggest that ferroptosis inducers are expected to be used in the treatment of pancreatic cancer.
2.3 Ferroptosis and renal cell carcinoma
Renal cell carcinoma originates from the renal parenchyma urothelial system and is a highly malignant tumor in the urinary system. Yang et al. [33] found that GPX4 is a key regulator of the ferroptosis signaling pathway in clear cell renal cell carcinoma. When compared with the other tumor cell from other tissues (lung cancer, colon cancer, central nervous system, melanoma, ovarian cancer, breast cancer, and leukemia), renal cells were more sensitive to ferroptosis induced with inhibition of GPX4. Renal cancer cells are induced by the hepatocyte factor -1β-1-acylglycerol-3 phosphate oxyacyltransferase 3 (AGPAT3) axis and the HIF-2α-HILPDA pathway, which can induce polyunsaturated fatty acyl lipid–enriched cells state, thereby increasing its susceptibility to ferroptosis [34]. Recently, Yang et al. [35] found that the sensitivity of renal cancer cells to ferroptosis is regulated by cell density and transcriptional regulator 1 (TAZ)-TAZ regulation of epidermal membrane protein 1 (EMP1)/NOX4 pathway [34, 35], suggesting that TAZ is a potential therapeutic target for ferroptosis.
2.4 Ferroptosis and breast cancer
Breast cancer is derived from breast epithelial tissue. Ma et al. [36] found that the lysosomal interfering agent siramesine and the tyrosine kinase inhibitor lapatinib can disrupt the iron homeostasis in breast cancer cells to generate reactive oxygen species and induce cell ferroptosis, and overexpression of trasnferrin receptor 1 (TfR1) or iron chelators can reduce siramesine and lapatinib-induced reactive oxygen species.
Some studies have shown that the formation of a complex between mucin 1C subunit and SLC7A11 can upregulate the expression of reduced glutathione and inhibit ferroptosis in triple-negative breast cancer cells [37]. Timmerman et al. [38] found a subpopulation of glutamine auxotrophic triple-negative breast cancer cells that were highly dependent on SLC7A11 acquires cystine for glutamine metabolism. The SLC7A11 inhibitor sulfasalazine can inhibit tumor growth by promoting ferroptosis. In addition, the activities of SLC7A11 and glutamate/cystine antiporter can be regulated by the Keap1/NRF2 redox pathway. Lanzardo et al. [39] believed that SLC7A11 is closely related to drug resistance and metastasis of triple-negative breast cancer cells. The increased expression of TFR1 in breast cancer cells is negatively correlated with the expression of estrogen receptor, and the high expression of TFR1 in breast cancer tissue is associated with poor prognosis of patients [40, 41].
2.5 Ferroptosis and bladder tumors
Intracellular iron concentration is closely related to the progression of bladder tumors. Martin-Sanchez et al. [42] analyzed the relationship between intracellular iron concentration and bladder tumor proliferation and found that when transferrin combined with iron, the free iron decreased in tumor cells, which was conducive to the proliferation of bladder cancer cells. When the application of gallium (Ga) to transferrin interferes with the binding of iron to transferrin, the intracellular free iron increases and thus inhibits the proliferation of bladder tumor cells. Mazdak et al. [43] found that the serum iron level of patients with bladder tumors was significantly lower than that of the normal control group, suggesting that the decreased serum iron level may be an important reason for the occurrence of bladder tumors. Tang et al. [44] proposed the phenomenon of ferritin phagocytosis, which releases intracellular free iron through ferritin and increases the content of intracellular free iron, which may play a role in inhibiting bladder tumors. The results suggest that activating ferroptosis can achieve ideal therapeutic effect on bladder tumors. These studies suggest that increasing intracellular iron concentration may help to inhibit bladder tumor progression.
2.6 Tumor-associated ferroptosis regulatory protein
2.6.1 SLC7A11 regulates ferroptosis
SLC7A11(also known as xCT) is the substrate-specific subunit of System Xc− responsible for the transport of cystine from the extracellular to the intracellular. The nuclear factor erythroid-like 2 (Nrf2) and transcription factor 4 (activating factor 4, ATF4) can induce SLC7A11 expression when cells are in a state of oxidative stress and L-cysteine deficiency [45]. Studies have found that SLC7A11 is highly expressed in tumor tissues, and that high expression of SLC7A11 can inhibit ROS-induced ferroptosis. p53 leads to cystine deficiency by inhibiting the expression of SLC7A11, which in turn increases the sensitivity to ferroptosis. Importantly, the survival and proliferation of SLC7A11-overexpressing cancer cells are dependent on glucose, such tumors may be sensitive to glucose-blocking drugs, also suggesting a role for SLC7A11 in modulating nutrient dependence and demonstrating another therapeutic strategy for tumors with high SLC7A11 expression [46].
2.6.2 p53 regulates ferroptosis
p53 is a widely recognized tumor suppressor that can induce senescence and programmed cell death in human cancer. It can affect ferroptosis of tumor cells through transcriptional or posttranslational mechanisms. Also, it can inhibit tumors by regulating cell cycle arrest, apoptosis, or premature aging.
Increasing the stability of wild-type p53 can promote the expression of its transcriptional target gene CDKN1A (encoding p21 protein), which can increase the intracellular glutathione level, inhibit the accumulation of ROS, and negatively regulate ferroptosis of cancer cells. Acetylation-deficient p53 increased the sensitivity of tumor cells to ferroptosis by inhibiting
Jiang et al. [47] found that three lysines in the DNA-binding domain of p53 were mutated to arginine (K117/161/162R, namely p533KR), p533KR can further restrict cystine uptake by inhibiting SLC7A11 gene transcription, make tumor cells more sensitive to oxidative stress-induced ferroptosis. Wang et al. [48] found that the site K98 in the DNA-binding domain of p53 is particularly important for the regulation of SLC7A11. Additionally, the mutant S47 of p53 fails to inhibit the transcription of SLC7A11 and induces ferroptosis resistance in hepatocellular carcinoma cells, increasing the risk of cancer in mice [49]. Moreover, p53 can make colon cancer cells insensitive to ferroptosis by inhibiting dipeptidyl peptidase 4 activity [50].
2.6.3 NRF2 regulates ferroptosis
NRF2 is an important transcriptional regulator in oxidative reactions [51], and its overexpression can inhibit apoptosis and lead to drug resistance in some tumors [52]. NRF2 plays an important role in protecting hepatocellular carcinoma cells from ferroptosis [22]. After treatment of hepatocellular carcinoma cells with Erastin and Sorafenib, p62 inhibits the degradation of NRF2 and induces NRF2 accumulation in the nucleus through the inactivation of Keap1, thereby regulating downstream gene transcription. Inhibition of NRF2 by the alkaloid trigonelline can induce ferroptosis in hepatocellular carcinoma cells, and combined use with chemotherapeutic drugs has the application prospect of overcoming tumor drug resistance [22]. Thus, activation of the p62-Keap1-NRF2 pathway can activate ferroptosis to reverse tumor chemotherapeutic drug resistance.
2.6.4 ACSL4 regulates ferroptosis
ACSL4 is expressed on the mitochondrial outer membrane and endoplasmic reticulum and can convert long-chain fatty acids into fatty acyl-CoA, which plays an important role in lipid biosynthesis and fatty acid degradation. ACSL4 increases the sensitivity of cells to ferroptosis by accumulating long-chain polyunsaturated ω-6 fatty acids in the cell membrane [10]. Studies have shown that in basal-like breast cancer cell lines, liver cancer cells, leukemia cells, and prostate cancer cells, the expression level of ACSL4 can be used to predict the sensitivity of tumor cells to ferroptosis [10, 28, 52]. The results suggest that ACSL4 is expected to be a potential target and biological marker for targeting ferroptosis in tumor therapy.
2.6.5 GPX4
Glutathione peroxidase 4 (GPX4) is the only glutathione peroxidase that can use glutathione as the electron donor to reduce the toxic lipid hydroperoxides in biofilms to corresponding alcohols. Tumor cells with high GPX4 show impaired proliferation, decreased proliferation, and inhibition of angiogenesis. Overexpression of GPX4 in hepatocellular carcinoma cells can inhibit the formation and development of hepatocellular carcinoma by decreasing ROS level, increasing glutathione and decreasing the formation of the cytokine-cytokine IL-8, inhibiting cell cycle progression and cell migration [53]. Based on the clinicopathological study and in vitro cell death analysis, it was found that overexposure to GPX4 in diffuse large B-cell lymphoma (DLBCL) inhibited ROS-induced ferroptosis [54]. GPX4 is a major target molecule for ferroptosis inducers such as erastin and RSL3. Erastin inhibits GPX4 activity by depleting glutathione, whereas RSL3 can directly inhibit GPX4 activity. In addition, previous studies have demonstrated that GPX4 can induce ferroptosis in mouse tumor xenograft models [33].
2.6.6 FSP1 inhibits ferroptosis
FSP1 inhibits ferroptosis FSP1 was originally named mitochondrial apoptosis-inducing factor 2 (AIFM2), as the newly discovered GPX4-independent ferroptosis inhibitor, and its expression is closely related to the sensitivity of tumor cells to ferroptosis. Recently, Doll’s group and Bersuker’s group simultaneously screened independently and found that FSP1 levels are different in different cell lines, and the resistance level of various tumor cell lines to ferroptosis was positively correlated with the FSP1 level, which results in differences in the sensitivity of different tumor cell lines to ferroptosis [18, 19]. Additionally, it was also reported that FSP1 was a novel KEAP1/NRF2 target gene regulating ferroptosis and radioresistance in lung cancers [55]. These achievements provide important evidences for the development of drug-targeted ferroptosis in tumors.
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3. Ferroptosis and neurodegenerative diseases
Iron homeostasis is critical for brain and neural development and cognitive function, especially in the fetal or early neonatal period, iron deficiency can severely affect neurodevelopment, leading to impaired memory and learning [56]. Iron accumulates gradually in the brain with age, and accumulation studies have shown that iron accumulation is related to neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis [57]. In recent years, studies have found that there are main characteristics of ferroptosis such as increased lipid peroxidation, decreased glutathione, and GPX4 inhibition in neurodegenerative diseases and cognitive impairment. The use of ferroptosis inhibitors can effectively protect neurons and improve cognitive function. Related research progress is shown in Table 2.
| Diseases | Related studies | References |
|---|---|---|
| Alzheimer’s disease | Overexpression or increase of phosphorylated tau protein can induce neuronal ferroptosis, and α-lipoic acid can inhibit tau protein-induced ferroptosis | [63] |
| Hippocampal neuronal death and cognitive decline in brain | [68] | |
| Ferritin levels in cerebrospinal fluid can predict the progression of Alzheimer’s disease | [73] | |
| Parkinson’s disease | Activation of protein kinase C triggers ferroptosis | [79] |
| Serine/threonine protein kinase is involved in Erastin-induced ferroptosis | [85] | |
| Astrocytes provide neurons with GSTM2 to protect neurons from oxidative damage | [81, 82, 83] | |
| Amyotrophic lateral sclerosis | Neuronal | [68] |
Table 2.
Ferroptosis in neurodegenerative diseases.
Gpx4: glutathione peroxidase 4; GSTM2:Glutathione S-transferase Mu2.
3.1 Ferroptosis and Alzheimer’s disease
Patients with Alzheimer’s disease possess destabilization of metal metabolism, inflammatory response, oxidative stress, abnormal mitochondrial function, and impaired glial function [57, 58]. Studies have shown that iron accumulation in the brain is associated with the formation of senile plaques and neurofibrillary tangles, elevated iron levels in the brain increase the risk of Alzheimer’s disease, and ferritin levels in cerebrospinal fluid predict the progression from mild cognitive impairment to Alzheimer’s disease [59, 60, 61]. The chronic inflammation, neuronal degeneration, and lack of downstream apoptosis indicators associated with Alzheimer’s disease suggest the existence of other cell death manners such as ferroptosis in Alzheimer’s disease [62, 63, 64].
An investigation on the Gpx4-specific knockout mice in cerebral cortex and hippocampal neurons exhibited cognitive decline and degeneration of hippocampal neurons in the water maze test, after feeding with a vitamin-E-rich diet or Lip-1, the neuronal degeneration of the mice was significantly alleviated, suggesting that ferroptosis plays an important role in neuronal degeneration [62]. Another study found that overexpression or hyperphosphorylation of tau protein can induce ferroptosis in neurons, while α-lipoic acid can rescue neurons by downregulating TfR1, reducing p38 phosphorylation level, and upregulating the expression of Slc7a11 and Gpx4 [63]. In addition, feeding with a deuterated polyunsaturated fatty acid in a mouse model of Alzheimer’s disease can alleviate the lipid peroxidation of tissues and reduces β-amyloid deposition [64, 65].
3.2 Ferroptosis and Parkinson’s disease
An important feature of Parkinson’s disease is iron accumulation in neurons and substantia nigra glia, and the concentration of iron accumulation is positively correlated with disease severity [66, 67]. Significant changes in iron regulatory protein 1(IRP1), divalent metal transporter 1(DMT1), and other key proteins involved in iron homeostasis have been observed in Parkinson’s disease patients and mouse models [68, 69, 70, 71, 72]. The τ knockout mice developed parkinsonism with iron accumulation in the nigra, which can be inhibited by iron chelators [73, 74, 75]. In addition to elevated iron levels in the substantia nigra pars compactus, parkinsonism is also characterized by ferroptosis, such as reduced glutathione depletion and lipid peroxidation [76], iron chelators and N-acetylcystine can alleviate and improve some of the symptoms in patients and mouse model of Parkinson’s disease [77, 78], suggesting that ferroptosis may be involved in the occurrence and development of Parkinson’s disease.
Do Van et al. [79] found that dopaminergic neurons’ ferroptosis occurred in LUHMES cell lines, brain tissue slices cultured
3.3 Ferroptosis and amyotrophic lateral sclerosis
Iron accumulation occurred in the brain of amyotrophic lateral sclerosis model mice [84, 85, 86], and the therapeutic effect of iron chelators confirms the role of iron in the pathogenesis of amyotrophic lateral sclerosis. Patients with amyotrophic lateral sclerosis have increased lipid peroxidation in cerebrospinal fluid and plasma and decreased levels of reduced glutathione in the motor cortex, suggesting the possibility of ferroptosis occurrence [87, 88]. Knockout of Gpx4 in mouse neurons can cause symptoms of amyotrophic lateral sclerosis, mainly characterized by rapid paralysis, severe muscle atrophy, and death, which is related to ferroptosis of spinal motor neurons [62]. However, no significant neurodegeneration was observed in the cortex of neuronal Gpx4-inducible knockout and other Gpx4-selective cortical neuron knockout mouse models. It is suggested that Gpx4 plays an important role in the process of ferroptosis of spinal motor neurons [62].
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4. Ferroptosis and cardiovascular disease
Cardiomyocyte and neuron death in cardiovascular and cerebrovascular diseases are related to a variety of cell death manners, and ferroptosis is also involved. The relevant research progress is shown in Table 3.
| Diseases | Related studies | References |
|---|---|---|
| ischemia–reperfusion | In an isolated mouse cardiac ischemia–reperfusion model, inhibition of glutamine metabolism can attenuate ferroptosis-induced cardiac injury | [93] |
| ferroptosis inhibitors and iron chelators can effectively alleviate myocardial injury induced by cardiac ischemia–reperfusion in mice | [89] | |
| Doxorubicin-induced myocardial injury | Doxorubicin induces ferroptosis in cardiomyocytes via heme oxygenase; iron accumulation and lipid peroxidation mainly occur in mitochondria | [89] |
| Heme oxygenase inhibitors, ferroptosis inhibitors, mitochondrial antioxidant inhibitors, iron chelators, etc., can effectively reverse doxorubicin-induced myocardial injury | [89] | |
| Myocardial damage after heart transplantation | Ferroptosis regulates neutrophil recruitment after cardiac transplantation in mice | [105] |
| Ischemic stroke | Hypoxia-inducible factor prolyl hydroxylase may be a potential target of iron chelators to inhibit neuronal ferroptosis | [115] |
| Inhibition of ferroptosis protects neurons in mice with middle cerebral artery occlusion, and the interaction between iron and tau protein is pleiotropically regulated | [105] | |
| Hemorrhagic stroke | (−)-Epicatechin alleviates early brain injury in hemorrhagic stroke by reducing cerebral iron accumulation and ferroptosis-related protein expression | [116] |
| Ferroptosis inhibitors attenuate neuronal death in brain slices and in a mouse model of hemorrhagic stroke | [117, 118] | |
| Increased glutathione peroxidase 4 expression can avoid neuronal ferroptosis and improve prognosis | [119] |
Table 3.
Ferroptosis in cardiovascular and cerebrovascular diseases.
4.1 Ferroptosis and cardiovascular disease
In some pathological conditions, the heart exhibits excessive accumulation of iron, production of reactive oxygen species, and pathological transformation of membrane lipids, which are all important factors that constitute ferroptosis. So far, there are few studies directly linking ferroptosis with cardiovascular disease. The latest research results of the Wang group in 2019 revealed the important role of ferroptosis in cardiomyopathy and ischemia–reperfusion-induced cardiac injury for the first time [89]. This landmark discovery provides a new strategy for the prevention and treatment of cardiomyopathy and other heart diseases.
4.1.1 Ferroptosis is involved in tissue and organ induced by ischemia: reperfusion damage
During cardiac ischemia–reperfusion, excess reactive oxygen species, lipid peroxidation, and iron accumulation caused by the release of iron in heme will be produced [90, 91, 92]. Gao et al. [93] established an isolated mouse cardiac ischemia–reperfusion model and found that inhibiting glutamine metabolism could inhibit ferroptosis, thereby reducing cardiac injury. Fang et al. [89] established an in vivo myocardial ischemia–reperfusion model and found that Fer-1 and iron chelators can significantly reduce the acute and chronic cardiac injury of ischemia–reperfusion, confirming the role of ferroptosis in cardiac ischemia–reperfusion injury. In addition, ferroptosis is also involved in ischemia–reperfusion injury in the kidney [94] and liver [95].
4.1.2 Ferroptosis is involved in antitumor drug-induced myocardial injury
As a broad-spectrum antitumor drug, adriamycin was limited in clinical use due to its cardiotoxicity. Autophagy, apoptosis, necrosis, and other cell death type are involved in the myocardial injury caused by adriamycin [96, 97, 98]. Fang et al. [89] found that ferroptosis occurred in cardiomyopathy induced by doxorubicin in mice deficient in apoptosis and proposed that heme oxygenase 1 (HO-1) may be a key regulator in this procedure. They also found that iron accumulation and lipid peroxidation in cardiomyocytes occur in mitochondria and the mitochondria-targeting antioxidant MitoTEMPO can effectively inhibit ferroptosis and protect the heart.
4.1.3 Ferroptosis is involved in myocardial injury after heart transplantation
In Li’s studies [99], it was found that the recruitment of neutrophils after heart transplantation is regulated by ferroptosis. The donor heart can induce ferroptosis in cardiomyocytes due to ischemia, hypoxia, and other reasons after transplantation, and the cellular contents are released and recruit neutrophils to produce necrotic inflachannelled by TLR4 / Trif/type I interflammatory via TLR/Trif/type I interferon pathway. Fer-1 can reduce arachidyl phosphatidylethanolamine after heart transplantation and decreased cardiomyocyte death and neutrophil recruitment.
4.1.4 Ferroptosis and diabetic cardiomyopathy
In diabetes, persistent high blood glucose and insulin resistance can cause a vicious circle by altering cellular metabolism, promoting the accumulation of peroxidation and the death of cells. So far, diabetes has been verified to be associated with abnormal iron metabolism. For example, systemic iron overload can contribute to abnormal glucose metabolism and the onset of type 2 diabetes (T2DM) [100] and aggravate insulin resistance [101]. Recently, Cai group [102] identified the role of ferroptosis in DCM and reported that Nrf2 activation by sulforaphane inhibited ferroptosis and prevented DCM, suggesting that it is feasible to treat DCM by inhibiting ferroptosis. Due to the limited regenerative capacity of the myocardium in mammalian adult hearts, inhibition of cardiomyocyte death might be one of the important ways to alleviate DCM [103]. In our studies, we induced DCM models in diabetic C57BL6 mice and treated with canagliflozin and found that canagliflozin mitigates ferroptosis and improves myocardial oxidative stress in mice with diabetic cardiomyopathy [104]. Taken together, taking ferroptosis as the starting point may provide a new strategy for the prevention and control of DCM.
4.2 Ferroptosis and cerebrovascular disease
Both ischemic stroke and hemorrhagic stroke can lead to neuronal ferroptosis [105, 106].
4.2.1 Ferroptosis and ischemic stroke
Before the discovery of ferroptosis, iron accumulation in clinical and animal models of ischemic stroke has been shown to aggravate neuronal damage during reperfusion [107, 108, 109, 110]. Iron chelators can reduce the risk of post-ischemic stroke in experimental animals [111, 112, 113, 114]. Speer et al. [115] proposed that ferroptosis leads to neuronal death after cerebral ischemia, and hypoxia-inducible factor prolyl hydroxylase may be the target for the beneficial effects of iron chelators. Inhibition of ferroptosis in a mouse model can protect neurons from ischemia–reperfusion injury [105].
4.2.2 Ferroptosis and hemorrhagic stroke
Chang et al. [116] found that epicatechin could alleviate early brain injury in hemorrhagic stroke by reducing cerebral iron accumulation and ferroptosis-related protein expression. Later, they found that Fer-1 could alleviate hemoglobin-induced brain injury. Cell death in slices and alleviation of neuronal death in a mouse model of collagenase-induced hemorrhagic stroke [117]. At the same time, Zille et al. [118] found that ferroptosis inhibitors such as Fer-1 and deferoxamine can inhibit the production of ferroptosis in mice. The expression level of Gpx4 in rats with acute hemorrhagic stroke decreased sharply, and increasing the level of Gpx4 could avoid secondary ferroptosis injury in neurons and improve the prognosis of hemorrhagic stroke [119]. Therefore, the ferroptosis pathway may be involved in the process of neuronal death in stroke, and it is speculated that targeted inhibition of ferroptosis may be an effective treatment for alleviating stroke.
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5. Conclusion
Besides tumors, neurodegenerative diseases, cardiovascular and cerebrovascular diseases, ferroptosis has also been reported in liver diseases such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis [120, 121, 122, 123, 124].
ROS-induced ferroptosis can inhibit tumor growth and increase the sensitivity of tumor cells to chemotherapy and radiotherapy. Contrary to tumor treatment strategies, ferroptosis can promote the occurrence and development of neurodegenerative diseases and cardiovascular and cerebrovascular diseases. Therefore, relevant translational medicine research mainly focuses on the discovery of small molecules that can effectively inhibit ferroptosis. These small-molecule activators targeting ferroptosis can be used directly as chemotherapeutics, or as chemosensitizers in combination with chemotherapeutics. However, ferroptosis is complex in different types of tumors and different gene mutations (such as p53 or RAS mutations), and its feasibility in preclinical and clinical research needs to be further studied. Notably, the discovery of GPX4 pathway-independent FSP1 and the discovery of new mechanisms and targets such as CD8+ T cells inducing ferroptosis in tumor cells through the release of interferon-gamma [18, 19, 125], it provides a new perspectives and strategy for tumor treatment and drug discovery.
Iron accumulation and ferroptosis in the brain and nerve tissue have been proved to be closely related to Alzheimer’s disease and Parkinson’s disease. There is a direct relationship between the pathogenesis of various neurodegenerative diseases such as Parkinson’s disease and amyotrophic lateral sclerosis. At present, various clinical trials using iron chelators to treat neurodegenerative diseases are emerging, but there is still no effective treatment for stroke. Given the important role of ferroptosis in neuronal death after stroke, effective inhibition of ferroptosis is expected to provide a new strategy for preventing neuronal death caused by stroke.
Similar to the pathogenesis of neurodegenerative diseases, many cardiac diseases share common ferroptosis features, such as iron overload, oxidative stress, endoplasmic reticulum stress, and mitochondrial dysfunction. Previous studies by the author’s team suggest that ferroptosis inhibitors can effectively prevent and treat cardiomyopathy and heart failure induced by myocardial cell iron overload, doxorubicin-induced cardiotoxicity, and cardiac ischemia–reperfusion [89]. Five different approaches, including ferroptosis inhibitors, iron chelators, mitochondria-specific antioxidants, heme oxygenase 1 inhibitors, and low-iron diets, can effectively prevent ferroptosis in cardiomyocytes, thereby protecting the heart. And these ferroptosis inhibitors are relatively safe and feasible in mice. It provides an optimistic prospect for clinical translational research on targeting ferroptosis to prevent and treat heart disease [121, 126, 127].
With a view to clinical translation, here are some issues need to be considered, e.g., which disease or tumor needs to be considered for ferroptosis-targeted therapies? In clinical or preclinical experiments, drugs targeting ferroptosis need high tissue-organ specificity and fewer adverse reactions, and nano-targeted drug delivery systems have shown some advantages [128, 129]. Although there is a growing awareness of ferroptosis, some key scientific questions related to ferroptosis still need to be resolved, such as what are the key executive molecules in ferroptosis? To what extent is lipid peroxidation related to ferroptosis? Does ferroptosis exist in physiological processes? Is ferroptosis conservative in the evolutionary process? We are well aware of the long road ahead. With the deepening and expansion of ferroptosis-related research, we believe that it will provide a basis for the clinical translation of targeting ferroptosis to prevent and treat major chronic diseases.
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Acknowledgments
This work was supported by grants from Medicine and Health Science and Technology Plan Projects of Zhejiang Province (YS, 2020PY029), Science and Technology Innovation Special Project of Jiaxing Science and Technology Bureau (YS, 2020AY30003), Zhejiang Provincial Health Science and Technology Program of Traditional Chinese Medicine (YS, 2021ZB283), Zhejiang Basic Public Welfare Research Program (YS, LGF18H200004), and Jiaxing Key Laboratory of Diabetic Angiopathy.
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