Oxidative Stress-Induced Ferroptosis

Abstract

Oxidative stress is viewed as a cause of damage to proteins, DNAs, and lipids, therefore inducing alteration in their function and ultimately leading to cellular damage. Lipid peroxidation often occurs under oxidative damage conditions. A high rate of lipid peroxidation can cause cell death, such as apoptosis, necrosis, and ferroptosis. Different from apoptosis and autophagy, ferroptosis is a kind of regulated cell death (RCD) that features the dysfunction of lipid peroxide, resulting in tumors, inflammatory, and cardiovascular diseases. Extensive studies suggest that ferroptosis plays a pivotal role in some human diseases, thus providing novel opportunities for therapy. We focus on the physiological and pathological mechanisms of oxidative stress and ferroptosis and finally discuss the prospect and challenge of therapeutic strategies toward ferroptosis in several diseases.

1. Introduction

Oxidative stress was described as a kind of imbalance between oxidant and antioxidant systems. It is characterized by the weakened ability of the endogenous system to defend against the oxidative attack toward several target biomolecules [1]. The field of oxidative stress research includes biochemistry, physiology, pathophysiology, and cell biology, furthermore, medicine, health, and disease research may also involve oxidative stress research. Oxide metabolism complements the details of hydroperoxide metabolism in mammalian organisms and the relationship in bioenergetics [2].

Both reactive oxygen and nitrogen species can induce oxidative stress, which is traditionally viewed as a cause of damage to proteins, DNAs, and lipids, therefore inducing alteration in their function and eventually leading to cellular damage [3]. Proteins are mainly functional biomolecules that drive cellular activity. Oxidative damage to proteins may lead to protein dysfunction [4]. DNA damage can be caused by reactive oxygen species (ROS) radical and may do harm to mutations, epigenetic changes, and genetic instability [5, 6]. Oxidative stress can damage several types of oncogenes and antioncogenes and then cause mutations that are known to trigger cancer. Lipid peroxidation often occurs under the condition of oxidative damage and it usually locates on the cellular membrane, finally results in disability of membrane properties [7]. Many other molecules may also be damaged by the reactive end products of lipid peroxidation. Low lipid peroxidation leads to the adaption of cell defense mechanisms, while a higher rate of lipid peroxidation can cause cell death, such as apoptosis, necrosis, and proptosis.

The field of ferroptosis has seen great growth in the past few years. Ferroptosis is a kind of regulated cell death (RCD) that was found to have a close connection to iron and lipid metabolism [8]. It features the clearing dysfunction of lipid peroxide, the existence of redox-active iron, and the oxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids [9]. This modality of cell death has been proved to be regulated by multiple cellular metabolic pathways, including iron handling, redox homeostasis, mitochondrial activity, and metabolism of many other molecules such as amino acids and lipids. Furthermore, it also exists in various signaling pathways linked to disease. Although the idiographic function of ferroptosis remains poorly researched, its connection with diseases, such as tumors, inflammatory, and cardiovascular diseases (CVDs), has been widely discussed.

From invertebrates to vertebrates, oxidative stress seems to play an important role in functioning as a regulator in both physiological and pathological mechanisms. Here, we will summarize the features, production process, function, and mechanisms of oxidative stress, discuss its relevance with lipid peroxidation and ferroptosis, and raise some unsolved issues of ferroptosis.

2. Generation of reactive oxygen species and antioxidant system

2.1 Generation process of ROS

ROS are radicals, ions, or molecules and are some kinds of the most familiar oxidants in cells. ROS can be divided into two categories: free oxygen radical ROS and non-radical ROS, which are formed by the partial reduction of molecular oxygen to superoxide, hydrogen peroxide, lipid peroxides, or the corresponding hydroxyl and peroxyl radicals.

There are also endogenous and exogenous ROS. Endogenous ROS are often produced by mitochondria, peroxisomes, and inflammatory cells [10]. Mitochondria are important cellular organelles and major sites of the production of ROS. When mitochondrial reactive oxygen species (mtROS) accumulate, p38 has been proven to be activated, then leading to paraquat (PQ)-induced proptosis [11]. The production of mtROS has also been identified to be essential for signaling in antigen-specific T cell activation, while dysfunction of mitochondria in T cells has been seen as feature of some autoimmune diseases in humans [12]. ROS production in peroxisomes can be regulated by post-translational modifications [13]. In recent years, diverse evidence has indicated that peroxisomes are important cellular sources of various signaling molecules, including ROS. Peroxisomes take part in different processes of high physiological importance and might be crucial in cellular redox homeostasis maintenance. Inflammation is a basic defensive response toward harmful stimulation, but the overactivation of inflammatory responses is related to most kinds of human diseases [14]. Inflammatory cells can produce ROS through the reduction of the molecular oxygen. ROS at a proper level can function as critical signaling molecules in the regulation of various physiological functions, including inflammatory responses. However, overproduced ROS have a toxic impact on cells and can straightforwardly oxidize biological molecules, such as proteins, DNAs, and lipids, further exacerbating the development of inflammatory responses and causing various inflammatory diseases.

ROS have been reported to be closely linked with inflammation and tumor survival and invasion, furthermore, leading to the happening of tumor development, cardiovascular disorders, neurodegenerative diseases, and other pathologies.

2.2 Antioxidant systems

Antioxidant systems have been greatly researched in recent years for their protective roles in oxidative stress caused by ROS. They have been defined as substances that have the ability to reduce oxidant species, which means lower oxidative stress, decreased DNA mutations, and less cell damage [15].

There are several classification criteria, such as enzymatic and non-enzymatic, endogenous and exogenous. The earliest type of antioxidant system identified as a mechanism against oxidative stress is featured by preventing the occurrence of ROS and blocking and capturing radicals that have formed. Another important type of antioxidant system in cells is identified as a repairing process, which can eliminate the damaged biomolecules before alteration of cell metabolism [16]. However, with continued free radical action, the capacity of the defensive systems against ROS can be reduced, inducing the occurrence of some human diseases [17].

When cells are exposed to harmful ROS, a series of reactions and induces activation of internal defensive mechanisms (enzymatic or non-enzymatic) will be caused. Several antioxidants, which can remove reactive species and derivatives, have been explored for their beneficial effects against oxidative stress. Antioxidant systems consist of enzymatic and non-enzymatic antioxidants, but the main burden of antioxidant defense is shouldered by enzymatic antioxidants.

2.2.1 Enzymatic antioxidants

The major role in antioxidant defense is conducted by antioxidant enzymes, not by the small molecular antioxidant compounds. Superoxide dismutase (SOD), glutathione reductase (GR), and catalases (CAT) are well-known antioxidant enzymes, which provide effective protection against oxidative stress [18].

SODs were first reported half a century ago by McCord and Fridovich. It is a metalloenzyme known as one of the most effective enzymatic antioxidants found in subcellular compartments and protects cells from the toxic effects of overproduced ROS [19]. SODs can decompose superoxide into oxygen and hydrogen peroxide and help prevent the transition metal-catalyzed formation of hydroxyl radicals. According to different metal cofactors, there are three isoforms of SOD enzymes, categorized as Cu/Zn-SODs, Mn-SODs, and Fe-SODs [20]. There also are extracellular SODs which can prevent endothelial cells from dysfunction by protecting against NO inactivation.

Glutathione (GSH)/glutaredoxin (GRX) system is one of the main cellular antioxidant pathways. In the GSH/GRX system, glutathione reductase functions to maintain the supply of reduced glutathione that acts importantly in the balance of cellular reactive oxygen species and then can further reduce oxidized GRX [21, 22]. In addition, it can transform toxic substances such as hydroxy peroxide into nontoxic metabolites in body homeostasis. GR is known as one of the most abundant reducing thiols in most cells and is known for its excellent antioxidant properties. Therefore, it can have a significant impact on cancer development.

Catalase has been studied extensively. It can be divided into several categories: bifunctional catalases, monofunctional catalases, and manganese-containing catalases [23]. CAT is an enzyme that has a tetrameric heme group and is an antioxidant enzyme that can convert hydrogen peroxide to water and oxygen rapidly. It has been proven to be effective on some toxic compounds via peroxidative reaction. CAT has been treated as a cancer therapeutic which has been widely studied to play a role in reducing oxidative stress and hypoxia in tumor microenvironment (TME) [24], both of which are hypothesized to decrease tumor growth.

2.2.2 Non-enzymatic antioxidants

The non-enzymatic antioxidants are characterized by molecules that can rapidly inactivate oxidants and radicals, including GSH and uric acid (UA).

GSH is composed of three amino acids: cysteine, glycine, and glutamic acid. In physiological conditions, it exists in many different tissues and acts as an antioxidant [25]. GSH in the human body is present in several redox forms, among which the most famous are reduced GSH and oxidized glutathione (GSSG). GSH in different cells has cellular type-special concentration and role. Besides being an effective antioxidant, it has many other functions not related to defense against ROS, for example, it also works in the repair processes of cellular damage.

Uric acid, chemically characterized as an antioxidant in the human plasma, both correlates and predicts the development of hypertension, obesity, and CVDs, conditions associated with oxidative stress [26]. It is also widely accepted that intracellular uric acid can defense oxidative stress via preventing ROS generated by xanthine oxidase. In prior studies, uric acid suppressed ROS accumulation and protected against ischemic neuronal injury [27]. Furthermore, it can also protect the erythrocyte membrane from lipid oxidation by eliminating free radicals.

3. Lipid peroxidation and ferroptosis

3.1 Lipid peroxidation

An increasing number of research have implicated lipid peroxides as key mediators in some pathological conditions, including inflammation, neurodegenerative disease, cancer, as well as cardiovascular diseases. In addition, lipid peroxidation is one of the crucial downstream features of ferroptosis, which is identified as a novel form of non-apoptotic RCD. Lipid peroxidation can be classified into two categories: lipid endoperoxides and lipid hydroperoxides. Lipid endoperoxides have been extensively researched as the pivotal intermediates in the generation of prostaglandins while recently, lipid hydroperoxides have also been considered as the key mediators in cell death and diseases [28].

3.2 Relationships between ferroptosis and other types of cell death

Ferroptosis is a new type of oxidative stress-dependent RCD, associated with iron overload and lipid peroxidation, then resulting in the accumulation of lipid hydroperoxides which can cause cell death.

3.2.1 Ferroptosis and autophagy

Autophagy is an evolutionarily conserved cellular process that is capable of degrading various long-lived proteins and biological molecules through the lysosomal pathway [29]. Autophagy has been extensively studied as a pivotal cellular response, and it is described to be involved in many diseases. Recently, ferroptosis was found to depend on autophagy. An increasing number of studies focused on the relationship between ferroptosis and autophagy. Recently, it has been suggested that ferroptosis and autophagy can synergize with each other.

The overactivation of autophagy has been confirmed to be induced by the ferroptosis inducers erastin [30]. Furthermore, autophagy triggers iron-dependent ferroptosis by degradation and release of ferritin and induction of the expression of transferrin receptor 1(TFR1) [31, 32, 33]. Remarkably, nuclear receptor coactivator 4(NCOA4)-mediated autophagy promotes ferritin phagocytosis to degrade and then release ferric ions, leading to the accumulation of autophagic vesicles. Therefore, NCOA4 overexpression can increase ferritin degradation via transporting excess ferric ions into the cytoplasm, causing oxidative stress responses and inducing ferroptosis in cells. Deficiency of autophagy causes decreased intracellular iron and reduced lipid peroxidation, which can prevent cell death from erastin-induced ferroptosis. As a result, induction of autophagy-dependent ferroptosis has also been suggested as a possible antineoplastic strategy.

These findings provide a novel understanding of the interplay between ferroptosis and autophagy. However, this interactive relationship still remains controversial, and the autophagy-inducing mediator is unknown.

3.2.2 Ferroptosis and apoptosis

Apoptosis is a kind of RCD and is considered a vital component of various physiological processes, such as normal cell turnover and development of immune systems [34]. In normal cells, apoptosis occurs when there is serious damage or protein misfolding, including an imbalance in apoptotic factors and genetic mutations. While in tumor cells, the genetic variations result in the molecular misfunction that inhibits cell division and even induces apoptosis, thus unlimited cell division and cell death evasion exist.

P53 is an important tumor suppressor and nuclear transcription factor that regulates the expression of genes. It can regulate cell biological processes, promote ROS production, and trigger ferroptosis and apoptosis [35]. ROS may act as a bridge between apoptosis and ferroptosis [36]. There has been a study suggesting that the C/EBP-homologous protein/p53 upregulated modulator of apoptosis (CHOP/PUMA) axis can respond to ferroptosis inducers [37], which means the axis may play a role in ferroptosis agent-mediated sensitization to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Erastin and artesunate (ART) induced endoplasmic reticulum (ER) stress and also promoted the expression of PUMA via CHOP. Furthermore, cysteine dioxygenase type 1(Cdo1) can regulate cysteine metabolism, thereby affecting the capacity of cellular antioxidative, which makes Cdo1 in an important situation in promoting both ferroptosis and apoptosis [38]. It promotes ferroptosis via decreasing the number of antioxidants, leading to the cell membrane auto-peroxidation by the Fenton reaction. Cdo1 also can facilitate apoptosis mainly through the production of cysteine metabolism, taurine, and decreased levels of antioxidants. It has been proved that the altered function of Cdo1 can be exhibited in many cancers, emphasizing its crucial role in tumor cell survival.

Evidence of the direct regulation of ferroptosis by p53 is still lacking. Thus, the specific regulatory mechanism still needs to be further studied.

3.3 Biological pathways involved in ferroptosis

It is widely accepted that excessive accumulation of iron can generate ROS through the Fenton reaction, resulting in lipid peroxidation and ferroptosis. The mechanism of ferroptosis is still unclear, but there are some hypotheses in recent research.

Through the initial study of the role of system Xc--GSH-GPX4 pathway in suppressing ferroptosis, phospholipid hydroperoxides (PLOOHs) have been identified as executioners of ferroptosis [39]. Overaccumulation of PLOOHs may possibly cause rapid and unrepairable damage to cell membranes, then leading to cell death. Glutathione peroxidase 4(GPX4) is one of the most well-known regulatory factors in the ferroptosis signaling pathways protecting cells from ferroptosis. GPX4 can inhibit the Fenton reaction by catalyzing the oxidation of GSH and removing lipid peroxides [40]. It is also a major PLOOH-neutralizing enzyme. Direct or indirect inactivation of GPX4 is a classic induction mechanism in ferroptosis. Previous studies revealed a general mechanism underlying erastin- or RSL3-induced ferroptosis. Both compounds can inactivate GPX4-RSL3. RSL3 can directly inactivate or deplete GPX4 to induce ferroptosis. Erastin inhibits the system Xc- and indirectly inactivates GPX4, resulting in the accumulation of lipid peroxides that promote ferroptosis [41].

In addition to the classical GPX4-dependent ferroptosis pathway, there are two newly discovered protecting pathways independent of GPX4, including the ferroptosis suppressor protein (FSP1)-ubiquinone (CoQ10) pathway [42] and guanosine triphosphate cyclohydrolase 1(GCH1) pathway [43]. With the help of NADPH, FSP1 can inhibit lipid peroxidation and ferroptosis by converting CoQ10 into ubiquinol, which can reduce lipid radicals directly [44, 45]. GCH1 can regulate the synthesis of tetrahydrobiopterin (BH4). Ferroptosis can be inhibited by selectively preventing the oxidation of lipids via GCH1-mediated BH4 production (Figure 1) [46].

Figure 1.

The mechanism of ferroptosis.

4. The potential therapeutic implications in diseases

Oxidative stress is associated with a great number of pathologies and is identified as one of the most primary causes of pathology. Basically, the contribution of oxidative stress to the etiology of those pathologies can be grouped into the following types: one is that oxidative stress is the primary cause of pathology; the other is it is the secondary contributor to different disease progressions, such as in inflammation, cancer, and CVDs. However, the actual role of oxidative stress in diseases remained unclear, this categorization above is tentative.

It has been proved that in many human diseases, oxidative stress often occurs secondary to the pathology caused by other factors. Oxidative stress can interfere with various signaling pathways and have effects on multiple biological processes via promoting inflammation, modifying proteins, inducing cell death, and many other biological mechanisms. These effects usually can accelerate pathological progression and worsen the symptoms of diseases.

In physiological conditions, the balance between oxidant and antioxidant compounds moderately improves prooxidants to produce mild oxidative stress, which means that the endogenous antioxidant systems are needed to intervene in the oxidative damage [47]. Strategies to enhance these defenses are principal to fundamental antioxidant therapy. With age growing, when the imbalance of endogenous antioxidants and repair systems happens, the issue of oxidative stress will become more acute. Therefore, various measures preventing or inhibiting these aggressive factors are aimed at decreasing disease incidence. Most studies toward the induction of antioxidant enzymes mainly focused on the regulatory mechanisms, the significance in diseases, and potential therapeutic inducers.

4.1 Cancer

ROS is involved in almost all phases of tumorigenesis, including transformation and growth of tumor cells, proliferation, invasion, and metastasis [48]. On the other hand, oxidative stress can also induce apoptosis and ferroptosis, and reduce the chance for transformation of tumor cells and thus prevent tumorigenesis. Therefore, oxidative stress is considered the main mechanism of radiation and chemotherapeutic drugs [49] and it is involved in almost all stages of cancer. Cancer cells can produce more ROS than normal cells. Therefore, cancer cells are exposed to increased oxidative stress in the loci. It can be observed that the oxidative markers increase in various cancers. For example, patients with non-small cell lung cancer (NSCLC) may exhale more H₂O₂ than normal individuals [50, 51]. Furthermore, compared to matched normal tissues, in prostate cancers [52] and lung cancers [53, 54], 8-hydroxy-2′-deoxyguanosine2 (8-OHdG) was observed to be significantly elevated, while it was also detected to elevate in breast cancer tissues [55].

In recent years, there has been emerging evidence indicating that ferroptosis-inducing agents toward ferroptosis-induced cell death in cancer may provide a promising strategy for cancer therapy [56]. Ferroptosis has been proved by Extensive studies that it plays a role in tumor suppression, thus providing novel opportunities for cancer therapy. Sorafenib can be described as a multiple kinase inhibitor, and it was reported to have the ability to induce ferroptosis and exert anti-tumor effects in many kinds of tumor cell lines, such as NSCLC [57], hepatocellular carcinoma cells [58], and human kidney cancer cells [59]. While we try to describe oxidative stress as harmful to the human body, it is true that it is exploited as a therapeutic approach to treat clinical conditions such as cancer, with a certain degree of clinical success.

4.2 Inflammation

Basically, many researchers have noticed that ROS and antioxidants can influence the immune systems in the human body. Inflammation is tightly connected with oxidative stress, which can trigger a series of transcription factors such as nuclear factor-kappa B1 (NF-κB1) [60], nuclear factor E2-related factor 2(Nrf2) [61], and pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) [62], thus leading to the different expressions of chemokines, inflammatory cytokines, and anti-inflammatory molecules.

The correlation between chronic inflammation and oxidative stress has already been confirmed. For example, in asthma [63] and allergic rhinitis [64], the imbalance between the activity of oxidative species, the promotors of oxidative damages, and the antioxidative defense is involved. Oxidative stress disrupts the cell signaling pathways and impairs arachidonic acid (AA) metabolism, thus enhancing airway and systemic inflammation [65]. It was also stated that allergic conditions can be initiated by the generation of TH1/TH2 cytokines [66], which are associated with oxidative stress-induced inflammation. Pterostilbene (Pts) alleviates oxidative stress and allergic airway inflammation through the regulation of AMPK/Sirt1and Nrf2/HO-1 signaling pathways [67]. Lycopene has high antioxidative activity, and there are results indicating that a daily dose of lycopene can exert an in vivo antioxidative effect against exercise-induced asthma (EIA) in some patients [68].

Redundant ROS induces oxidative stress and then consumes antioxidants in cells, which may further aggravate the production of lipid peroxidation and inflammatory responses [69]. Lipid peroxidation, in turn, can drive the increase of modified low-density lipoprotein (LDL), which can promote inflammation to some extent via macrophage polarization. Therefore, lipid peroxidation can be observed in many kinds of physiological conditions in different diseases, such as cell death and inflammatory responses in the pathophysiology. Aldose reductase (AR) can catalyze the limiting step of polyol pathway of glucose metabolism [70, 71]. Except for the ability to reduce glucose to sorbitol, it also can reduce lipid peroxidation by deriving aldehydes and glutathione conjugates. Previous studies suggested that catalytic activity of AR plays a role in various inflammatory diseases such as sepsis, asthma, and atherosclerosis.

4.3 Cardiovascular diseases

Many studies have mentioned that iron was involved in the development of atherosclerosis (AS) by affecting the level of lipid peroxidation in vivo. Ferroptosis connected with lipid peroxidation and iron deposition is prominent in the progression of AS [72]. Ferritin and LDL-cholesterol levels showed a synergistic relationship with the incidence of CVDs [73, 74]. Iron-catalyzed free radical reactions generate ox-LDL in endothelial cells, smooth muscle cells, and macrophages, which are important risk factors in atherosclerotic lesions [75]. Transferrin is the major iron-binding molecule in plasma which has a mutual effect on transferrin receptor protein 1(TFR1). It may deliver extracellular Fe3+ into cells, leading to iron overload and increased cell susceptibility to ferroptosis [76]. Therefore, ferroptosis in epithelial cells, vascular smooth muscle cells, and macrophages may be deduced to be related to the destabilization of atherosclerotic plaque. As a result, lowering iron levels in plasma can be an effective intervention to prevent iron overload and atherosclerosis progression.

Stroke induces the interruption or reduction of brain blood in blood circulation, which is one major cause of death in the world. Ferroptosis has been proven to be involved in pathological cell damage in stroke [77]. As reported before, iron plays a part in many physiological processes, such as oxidative reaction, erythropoiesis, and immunity. It also consists of cytochromes a-c in the oxidative chain and adenosine triphosphate (ATP). However, disturbances of iron homeostasis lead to neuronal damage after ischemic injury [78, 79]. Iron leads to ferroptosis and neuronal injury by converting superoxide and hydrogen peroxides into reactive hydroxyl radicals which may do harm to cells and tissues [80]. As a result, iron is causally associated with lipid hydroperoxide production and disease incidence of ischemic stroke. Both basic and clinical research results reveal that dysregulation of lipid peroxidation induces stroke [81]. There is also a clinical study exhibiting that the average levels of lipid hydroperoxides in the plasma of stroke patients were higher than controls [82].

CVDs usually begin with vascular disorders and end with heart failure (HF), which is the common final clinical result of CVDs. It was demonstrated that ferroptosis is highly correlated with terminally differentiated cardiomyocyte death. Some studies showed that the increased levels of free iron pool and lipid peroxide indicate that ferroptosis is directly related to HF [83]. For example, a study has shown that ferroptosis plays a vital role in doxorubicin (DOX)-induced HF [84, 85]. DOX results in the degradation of cardiac heme and release of free iron via the accumulation of oxidized phospholipids in cells and overexpression of heme oxygenase 1(HO-1), which causes ferroptosis in cardiomyocytes, finally leading to HF. Therefore, inhibitors of ferroptosis or HO-1 can significantly prevent HF caused by DOX. Another study has shown the decreased levels of ferritin heavy chain 1(FTH1) in HF and that cardiomyocyte death can be caused by iron deposition and an increase in oxidative stress [86]. Decreased levels of FTH1 in cells will lead to disordered iron metabolism and accumulation of ROS, thus causing ferroptosis. So, regulating the upstream axis and thus altering the level of FTH1 can be a key regulatory strategy in treating HF.

These studies revealed that ferroptosis is related to the regulation of HF. Therefore, it is a promising therapy to trap ferroptosis to treat ferroptosis-associated cardio disorders.

4.4 Neurodegenerative disorders

Oxidative stress has been mentioned in the occurrence and progress of several neurodegenerative disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) [87, 88, 89]. Oxidative stress was widely accepted to modify the inflammatory response, including neuroinflammation. It can be inferred that oxidative stress and neuroinflammation are linked and can affect each other.

AD is defined by a gradual deterioration of cognitive capacities which can result from synapses degradation and neuron death, especially in the hippocampus [90]. ROS is generated when there is a disproportion between antioxidants and oxidants and then the processes mentioned above will primarily originate and even enhance. The reason for this can either be a free radical enhancement or a reduction in the defense of antioxidants. OS induced by ROS is also considered a critical factor in the pathogenesis of AD because of its relationship with the accumulation and deposition of β-amyloid [91]. PD happens when the substantia nigra pars compacta of the brain exhibit dopaminergic neuron loss [90]. ROS is generated mainly in mitochondria in the neurons and neuroglia cells. The main reasons why ROS is overproduced in the PD are neuroinflammation, mitochondrial dysfunction, increased levels of iron and calcium, etc. The degradation of dopaminergic neurons is connected with the overproduction and extreme accumulation of ROS, which may be related to both mitochondrial dysfunctions and inflammation [91]. Although the utter process that determines dopaminergic neuronal loss is not clearly researched, it has been suggested that ROS can be a key factor. However, there is still no exact therapy for PD. But to understanding the mechanisms of ROS related to PD’s evolution can aid the development of treatments (Table 1).

Disease	Relationship with ferroptosis	Potential therapeutic target
Lung cancer	RBMS1 regulates the translation of SLC7A11, reduces SLC7A11-mediated cystine uptake, and then promotes ferroptosis.	Targeting ferroptosis pathway is a potential strategy for the treatment of lung cancer.
Acute Myocardial Infarction	Oxidized phosphatidylcholine-containing phospholipids(OxPL) are generated during AMI and have negative effects on cardiomyocyte viability. Lipid peroxidation was found to be a key factor leading to oxidative damage of cardiomyocytes.	The use of therapeutics Targeting ferroptosis and using cyclosporine A together can be a promising strategy toward AMI.
Heart Failure	During heart failure, FTH expression is downregulated, and a large amount of ferrous ions are released, ultimately leading to ROS accumulation and iron death.	Overexpression of SLC7A11 in cardiomyocytes increases glutathione levels and prevents FTH-induced ferroptosis.
Atherosclerosis	The accumulation of lipid peroxides, restriction of glutathione synthesis, and disturbance of iron homeostasis are related to ferroptosis and then induce atherosclerosis.	Activating NRF2 and inhibiting ROS release and iron levels can inhibit ferroptosis.
Alzheimer’s disease	NOX4 induces ferroptosis in nerve cells by oxidative stress-induced lipid peroxidation via the damage of mitochondrial metabolism.; Intracellular accumulation of amyloid beta(Aβ) can also induce ferroptosis in nerve cells.	Targeting iron and ferroptosis could be a promising therapeutic option for AD.
Parkinson’s disease	Aggregate-membrane interaction can induce ferroptosis. α-synuclein oligomers further induce lipid peroxidation.	GSH and its related molecules may have neuroprotective effects in PD pathology.

Table 1.

Diseases caused by ferroptosis and potential therapeutic targets.

5. Conclusions and perspectives

Lipid peroxidation is one of the crucial downstream features of ferroptosis, leading to the happen of tumor development, CVDs, and other pathologies. We summarize the features, production process, function, and mechanisms of oxidative stress and relevant biological processes in this review. An in-depth understanding of the molecular mechanisms underlying lipid peroxidation-induced ferroptosis is provided. It is widely accepted that excessive accumulation of iron can generate ROS through the Fenton reaction, resulting in lipid peroxidation and ferroptosis. The mechanism of ferroptosis is still unclear, but there are some hypotheses in previous research which can help us to understand signaling pathways and defense mechanisms of ferroptosis. It has been proved that oxidative stress can interfere with various signaling pathways and have effects on multiple biological processes. The usage of antioxidants in prevention and treatment is still in dispute. While we try to describe oxidative stress as harmful to the human body, it is true that it is exploited as a therapeutic approach to treat clinical conditions such as cancer, with a certain degree of clinical success. The link between ferroptosis and therapeutic strategies is emerging, but the exact mechanism remains to be further observed experimentally. Further studies should explore how ferroptosis is tightly regulated to provide therapeutic strategies for targeting ferroptosis to treat human diseases, offering guidance in developing new targeted antioxidant drugs (Table 2).

Number	Recent study about ROS and ferroptosis
1	Snap25 attenuates neuronal injury by reducing ferroptosis in acute ischemic stroke.; Si, W., Sun, B., Luo, J., Li, Z., Dou, Y., & Wang, Q.; Experimental neurology, 367, 114,476.; DOI: 10.1016/j.expneurol.2023.114476
2	Cancer-associated fibroblasts impair the cytotoxic function of NK cells in gastric cancer by inducing ferroptosis via iron regulation.; Yao, L., Hou, J., Wu, X., Lu, Y., Jin, Z., Yu, Z., Yu, B., Li, J., Yang, Z., Li, C., Yan, M., Zhu, Z., Liu, B., Yan, C., & Su, L.; Redox biology, 67, 102,923.; DOI: 10.1016/j.redox.2023.102923
3	Quercetin Protects against MPP+/MPTP-Induced Dopaminergic Neuron Death in Parkinson’s Disease by Inhibiting Ferroptosis.; Lin, Z. H., Liu, Y., Xue, N. J., Zheng, R., Yan, Y. Q., Wang, Z. X., Li, Y. L., Ying, C. Z., Song, Z., Tian, J., Pu, J. L., & Zhang, B. R.; Oxidative medicine and cellular longevity, 2022, 7,769,355.; DOI: 10.1155/2022/7769355
4	Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis.; Qiu, B., Zandkarimi, F., Bezjian, C. T., Reznik, E., Soni, R. K., Gu, W., Jiang, X., & Stockwell, B. R.; Cell, 187(5), 1177–1190.e18.; DOI: 10.1016/j.cell.2024.01.030
5	APE1 inhibition enhances ferroptotic cell death and contributes to hepatocellular carcinoma therapy.; Du, Y., Zhou, Y., Yan, X., Pan, F., He, L., Guo, Z., & Hu, Z.; Cell death and differentiation, 31(4), 431–446.; DOI: 10.1038/s41418-024-01270-0
6	A guideline on the molecular ecosystem regulating ferroptosis.; Dai, E., Chen, X., Linkermann, A., Jiang, X., Kang, R., Kagan, V. E., Bayir, H., Yang, W. S., Garcia-Saez, A. J., Ioannou, M. S., Janowitz, T., Ran, Q., Gu, W., Gan, B., Krysko, D. V., Zhu, X., Wang, J., Krautwald, S., Toyokuni, S., Xie, Y., … Tang, D.; Nature cell biology, 10.1038/s41556-024-01360-8. Advance online publication.; DOI: 10.1038/s41556-024-01360-8
7	GAS41 modulates ferroptosis by anchoring NRF2 on chromatin.; Wang, Z., Yang, X., Chen, D., Liu, Y., Li, Z., Duan, S., Zhang, Z., Jiang, X., Stockwell, B. R., & Gu, W.; Nature communications, 15(1), 2531.; DOI:10.1038/s41467-024-46,857-w
8	Identification of a targeted ACSL4 inhibitor to treat ferroptosis-related diseases.; Huang, Q., Ru, Y., Luo, Y., Luo, X., Liu, D., Ma, Y., Zhou, X., Linghu, M., Xu, W., Gao, F., & Huang, Y.; Science advances, 10(13), eadk1200.; DOI:10.1126/sciadv.adk1200

Table 2.

Recent study about ROS and ferroptosis.

Acknowledgments

This study was supported by the National Natural Science Foundation of China (82273139), Shanghai Science and Technology Committee Rising-Star Program (22QA1408300), Excellent Talents Nurture Project of Shanghai Chest Hospital (2021YNZYY02).