Abstract
Ferroptosis is a type of cell death driven by iron overload and lipid peroxidation. It is considered a key mechanism in the development of various diseases such as atherosclerosis, Alzheimer, diabetes, cancer, and renal failure. The redox status of cells, such as the balance between intracellular oxidants (lipid peroxides, reactive oxygen species, free iron ions) and antioxidants (glutathione, glutathione Peroxidase 4), plays a major role in ferroptosis regulation and constitutes its principal biomarkers. Therefore, the induction and inhibition of ferroptosis are promising strategies for disease treatments such as cancer or neurodegenerative and cardiovascular diseases, respectively. Many drugs have been developed to exert ferroptosis-inducing and/or inhibiting reactions, such as erastin and iron-chelating compounds, respectively. In addition, many natural bioactive compounds have significantly contributed to regulating ferroptosis and ferroptosis-induced oxidative stress. Natural bioactive compounds are largely abundant in food and plants and have been for a long time, inspiring the development of various low-toxic therapeutic drugs. Currently, functional bioactive peptides are widely reported for their antioxidant properties and application in human disease treatment. The scientific evidence from biochemical and in vitro tests of these peptides strongly supports the existence of a relationship between their antioxidant properties (such as iron chelation) and ferroptosis regulation. In this review, we answer questions concerning ferroptosis milestones, its importance in physiopathology mechanisms, and its downstream regulatory mechanisms. We also address ferroptosis regulatory natural compounds as well as provide promising thoughts about bioactive peptides.
Keywords: ferroptosis, lipid peroxidation, iron chelation, bioactive compounds, cardiovascular diseases, neurodegenerative diseases
1. Introduction
Cell death is a physiological and pathophysiological process leading to human cell renewal. It is the final point of the cell cycle controlled by canonical mechanisms (apoptosis, necrosis) to more exotic ones such as efferocytosis, necroptosis, pyroptosis, parthanatos, and ferroptosis. Ferroptosis is an iron-dependent form of non-apoptotic cell death, characterized by lipid peroxidation due to glutathione depletion and a decrease of glutathione peroxidase 4 (GPx4) catalytic activity.
The mechanism leading to ferroptosis has evolved from a sequence of atmospheric and ecological events. Since the early days on earth, trace amounts of oxygen have been produced from photosynthesis. Then they became abundant after the Great Oxygenation Event [1], which was the starting point of free radicals forming inside eukaryotic cells [2]. Dioxygen (O2) is a strong oxidant that needs activation to be reactive. For example, O2 is the last acceptor of electrons and protons produced by the respiratory chain. Moreover, O2 drives the oxidation of iron, forming reactive oxygen species that, in turn, oxidize polyunsaturated fatty acids (PUFA) of the cell membrane. The abundant iron-dependent cell mechanisms made this oxidation phenomenon even faster [3]. Early cell studies suggested the evolution of defense mechanisms to counteract the iron/oxygen-driven lipid peroxidation or to cause cell death [4]. These defense mechanisms, referred to as antioxidant power, reside in the intracellular and extracellular environment under enzymatic and non-enzymatic forms.
Therefore, ferroptosis is an ancestral type of cell death discovered only in 2012 by Dixon et al. using pharmacological approaches [5]. Dixon et al. transpose this physiological mechanism to cancer therapy. The timeline of discoveries leading to the current definition of the ferroptosis mechanism is presented in Figure 1. Ferroptosis comes from the Latin word “Ferrum”, meaning “iron”, and the Greek word “ptosis”, which means “to fall” [6]. Between 2012 and 2022, the scientific interest in ferroptosis increased exponentially, with more than 5000 articles published, with about half published in 2022. Research concerning cancer therapy targeting ferroptosis has guided the development of many ferroptosis inducers [7,8]. According to PubMed statistics, 1264 articles concerning ferroptosis inducers were published; on the other hand, 522 articles about ferroptosis inhibitors are published in 2022 (www.pubmed.ncbi.nlm.nih.gov (accessed on 30 September 2022)). However, the implication and treatment of ferroptosis in several diseases is still an ill-defined subject.
Nature-derived antioxidants from various sources show great bioactivities with a broad application spectrum in the prevention and/or treatment of diseases related to oxidative stress. Their mechanisms of action are extensive and include notably the reduction/scavenging of reactive oxygen species (ROS), the inhibition of lipid peroxidation, and the chelation of free metal ions [9]. In addition, several studies demonstrated that many natural compounds could regulate ferroptosis and could be promising drugs for targeting ferroptosis-related pathologies. Among them, bioactive peptides are also considered antioxidant compounds. With their functional amino acid sequences, these peptides can react with all possible oxidants and inhibit or suppress their damaging activities [10]. However, the bioactive peptides and ferroptosis relationship are still unexplored avenues in the research.
In this review, we highlight the main cellular and molecular mechanisms through which ferroptosis is induced and/or inhibited and their relationship to cardiovascular and neurodegenerative diseases. In addition, we state here the antioxidant properties of naturally derived compounds and bioactive peptides that have promising effects on ferroptosis-related conditions.
2. Iron-Catalyzed Lipid Peroxidation in Cells
Iron is an important trace element for cell functions [26]. However, its distribution and content should be controlled constantly in order to prevent iron overload or iron deficiency-related diseases [27]. Iron is absorbed by the intestines at the duodenum and proximal jejunum level, where it exists in its ferrous (Fe2+) form because of the low pH (∼5–6) in the duodenum, mainly due to gastric acid. When absorbed, Fe2+ is oxidized to Fe3+ by blood proteins such as hephaestin and ceruloplasmin. The majority of iron is transported and stored as a complex with proteins. Indeed, in the bloodstream, Fe3+ binds to transferrin, which transports Fe3+ from the bloodstream to tissues. The transferrin–Fe3+ complex is endocytosed after binding to transferrin receptors on the plasma membrane of target cells. The low pH of the endocytosis vesicle associated with ferrireductase activity reduces Fe3+ to Fe2+. Inside cells, Fe2+ is stored in ferritin and/or within the labile iron pool (LIP) [28,29,30]. Free iron (Fe2+ and Fe3+) provokes harmful reactions with proteins, nucleic acids, and lipids in the plasma membrane. Notably, iron excess participates in lipid peroxidation via hydroxyl-dependent and hydroxyl-independent mechanisms [31]. In the first mechanism, Fe2+ is oxidized into Fe3+ by hydrogen peroxide H2O2 through the Fenton reaction that produces hydroxyl radical OH●. In cells, Fe3+ produced by the Fenton reaction can be reduced back to Fe2+ by the oxidation of O2●− to O2, originating a catalytic cycle [32]. The formed hydroxyl radical is a highly reactive oxidant (half-life of 10−9 s) extracting hydrogen atoms from lipid molecules, starting lipid peroxidation [33]. The process of lipid peroxidation involves three main steps: initiation, propagation, and termination (Figure 2). For initiation, the lipid (L-H) is converted to a radical (L●) by a highly reactive species such as the hydroxyl radical, which pulls a hydrogen atom. Then, during the propagation step, L● quickly reacts with dioxygen (O2) and thus forms a lipid peroxyl radical (LOO●), which in turn extracts hydrogen from another L-H to form lipid hydroperoxide (LOOH) and a new L●. This is the propagation step. Finally, the termination step happens when a high concentration of lipid radical species is reached, so the probability of a collision between them is high. When two radical lipid species interact (2L●, 2LOO●, L● + LOO●), a non-radical species is formed [34,35]. Lipid peroxidation forms a wide range of reactive aldehydes, such as malondialdehyde (MDA) and 4-hydroxynonenal (HNE), that can be mutagenic and carcinogenic [36,37,38]. If lipid peroxidation is not rapidly terminated, damage to cell membranes takes place. Moreover, lipid peroxidation is implicated in the initiation and development of pathologies such as atherosclerosis. Atherosclerosis is a cardiovascular disease induced by an accumulation of oxidized lipids in the vascular wall forming atherosclerotic plaques. The early stage of plaque formation involves the oxidation of low-density lipoproteins (LDL), which attract macrophages. Those macrophages phagocyte oxidized LDL forming foam cells that compose atherosclerotic plaques [39,40,41].
3. Ferroptosis, a Cell Death Type among Others
The definition of cell death was first coined in 1858 by the biologist Rudolf Virchow, but the apoptosis mechanism (programmed cell death) was only elucidated in the 20th century. Besides canonical mechanisms of cell death (apoptosis, necrosis), more exotic ones such as efferocytosis, necroptosis, pyroptosis, parthanatos, and ferroptosis have been described. These types of cell death exhibit some similar features but remarkable differences in terms of morphology, mechanisms, and consequences [42].
Apoptosis is a programmed cell death mechanism that occurs for advantageous reasons for the organism’s life cycle [43]. It plays an important role during embryonic development as it shapes formed organs [44]. Apoptosis is a “self-suicide” that can be triggered by either intrinsic factors (i.e., cell aging, mutations, toxic infection...) or extrinsic ones (i.e., adjacent cells, cytokines…) activating caspase enzymes [45]. These enzymes degrade proteins and start the cellular execution process with specific morphologies characterized by DNA fragmentation, chromatin condensation, nuclear fragmentation, cell shrinkage, and blebbing [46]. Finally, cell fragments are released in the form of apoptotic bodies, then engulfed by phagocytosis cells via a mechanism called “efferocytosis”. Furthermore, deCathelineau and Henson nicely described efferocytosis as the process where phagocytes take apoptotic cells to their grave [47]. Necrosis, on the other hand, stands on the opposite pole from apoptosis. It is often a deadly process for tissues and organs initiated by an unregulated degradation of cell components and induced by extrinsic factors such as mechanical injuries, heat shocks, and pathological infections [48]. The fate of a necrotic cell is characterized by the rupture of its membrane and the release of its components into the extracellular space [49]. Necroptosis is a programmed form of necrosis, which is not always detrimental to biological systems. On the contrary, it contributes to defense mechanisms against viral infections. When cells are unable to undergo apoptosis due to the inactivation of apoptotic proteins by viral proteins, necroptosis is activated, independently from caspases, by responding to a pro-inflammatory signal from macrophages [50]. During necroptosis, like during necrosis, ATP levels drop, and the cell membrane is ruptured, leading to product leakages but in a regulated manner that is still under investigation [51]. Pyroptosis also falls in the category of programmed cell death. It generally takes place in immune cells during pathogenic infections. It is initiated by the cell itself when it starts to assemble the inflammasome, defined as an agglomeration of proteins that promotes multiple pro-inflammatory pathways [52]. Like in apoptosis, caspases are then activated; however, blebbing does not appear, but membrane pores do, and as a result, all molecules are released outside cells [53]. Parthanatos is a caspase-independent cell death with certain apoptotic features [54]. It is induced by extreme DNA damage, which is directly recognized by intracellular enzymes that activate the expression of the DNA repair factor, poly-ADP ribose (PAR). The more extreme the DNA damage is, the longer and more branched PAR is and the more toxic effect it has on the cell. PAR can also bind and activate the apoptosis-inducing factor (AIF), leading to its translocation from the mitochondria to the nucleus to start chromatin condensation and large-scale DNA fragmentation. Cells finally die by losing their membrane integrity [55].
Ferroptosis is a regulated form of cell death characterized by lipid peroxidation catalyzed by iron overload. Although studies concerning its biochemical and morphological features are still in their early stages, its distinction from other types of cell death was obvious from the beginning of its discovery. Ferroptosis can propagate to adjacent cells, which are swollen, rounded up, and detached from each other [5,56,57]. Nuclear integrity is maintained, but chromatin condensation is missing during ferroptosis [58]. Mitochondrial alterations are the most obvious changes observed during ferroptosis. The mitochondria appear smaller with thicker membrane density and reduced crista that will eventually lead to its destruction [5,18,59,60]. In physiological conditions, mitochondrial iron content is regulated by iron exporters and mitochondrial ferritin. However, the mitochondrial iron content is very high in certain ferroptosis-related diseases or ferroptosis-induced cancer cells [61,62,63,64]. Iron overload is accompanied by an increase in mitochondrial ROS production and reduced mitochondrial glutathione (GSH) content [62,65,66]. Decreased mitochondrial potential and increased mitochondrial permeability are other ferroptosis signs [59,67]. Recently, Guo et al. showed that inhibiting the replication of mitochondrial DNA can induce ferroptosis [68]. Moreover, internal lysosomal autophagy of ferritin, so-called “ferritinophagy”, is also observed in ferroptotic cells [13,59]. Ferroptosis is similar to H2O2-induced necrosis by the rupture of the plasma membrane but, yet, is not accompanied by ATP depletion [5,69,70]. All in all, ferroptotic cells accumulate iron, lipid peroxides, oxidized NADPH, and glutamate. They are depleted in cystine/cysteine and GSH [60,71,72].
4. Physiological Regulation of Ferroptosis
For properly functioning cells, biomolecular regulations are fundamental processes that adapt to internal and external environments. For example, cell oxidation caused by aerobic respiration is a physiologic phenomenon that maintains cell redox homeostasis. Impairments in the homeostatic control between cell oxidation and reduction reactions cause oxidative stress, eventually leading to lipid peroxidation up to ferroptosis (Figure 3).
The regulation of intracellular iron content is an important factor for resisting ferroptosis. Iron content is regulated at gene, cytosolic, and plasma membrane levels. Indeed, the Iron Responsive element Protein 2 (IREBP2) gene encodes for the iron-responsive element binding protein (IRE-BP) that binds to iron-responsive elements (stem-loop RNA structures) of many genes such as ferritin heavy chain 1 (FTH1) and transferrin receptor (TFRC) to control cell iron homeostasis. Therefore, variants in the IREBP2 gene affect the physiological cell iron metabolism and can aid in ferroptosis [5]. Furthermore, in the cytosol, ferritinophagy is caused by the upregulation of autophagy-related proteins (ATG5 and ARC7) that release the ferritin-stored iron and, thus, induce ferroptosis [73]. Finally, at the plasma membrane level, a too-high activity of transferrin and transferrin receptors mediates ferroptosis by iron overload inside cells [74].
The hallmark of ferroptosis might also be modulated by enzymes implicated in lipid peroxidation processes. Indeed, several cells knockout for Acyl-CoA synthase long-chain family 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3), implicated in the oxidation of membranes constituted of poly-unsaturated fatty acids [75,76], and are resistant to ferroptosis. In addition, lipoxygenase (LOX) is a ferroptosis-promoting enzyme that oxidizes phosphatidylethanolamine found in cell membranes [77]. Indeed, LOX overexpression in human kidney cells results in their sensitization to ferroptosis [77]. Finally, Glutathione peroxidase 4 (GPx4), an antioxidant enzyme reducing peroxidized lipids, can prevent ferroptosis [78]. Indeed, among the eight human GPxs’, GPx4 is the only one that can reduce oxidized phospholipids present in membranes. Thus, its catalytic activity is critically important for cell health, and the conditional deficiency of GPx4 in cells causes ferroptosis [78]. GPx4 is a selenoprotein that requires selenocysteine for its antioxidant activity [79]. Yet, the synthesis of selenoproteins requires isopentenyl-PP, an intermediate by-product of the mevalonate pathway [80]. Moreover, the mevalonate pathway produces, in addition, the coenzyme Q10, which has an antioxidant function at the membrane level [72]. Thus, the depletion of selenium provokes ferroptosis due to GPx4 misfunctioning [81]. Moreover, the activity of GPx4 strongly relies on the content of glutathione (GSH), its cofactor, inside cells [21].
The synthesis of intracellular GSH requires cysteine [82], which can be either provided via the transsulfuration pathway where methionine is converted to S-adenosylhomocysteine and cysteine [71] or via transmembrane proteins responsible for intracellular cysteine transport such as the L-amino acid transporter (L-AT) or system Xc−. System Xc− is a glutamate/cystine antiporter critical for providing cystine to cells. Cystine is then reduced to cysteine required for GSH synthesis.
In summary, ferroptosis is a cell death type related to intrinsic cellular events that can be modulated by the cell’s autonomous properties, including iron metabolism and redox reactions. However, the discovery and understanding of ferroptosis are being initiated in several studies through the action of pharmacological ferroptosis inducers and inhibitors.
5. Pharmacological Modulation of Ferroptosis
5.1. Ferroptosis Inducers
Ferroptosis, as previously clarified, was first discovered as a novel therapeutic approach to killing cancer cells using pharmacological agents [5]. Nowadays, a variety of molecules are used to induce ferroptosis, whether to treat cancer or to clarify cell pathways implicated in ferroptosis induction and inhibition (Figure 4). Ferroptosis inducers are reviewed in several publications [69,83,84]. The two most popular targets for ferroptosis inducers are system Xc− and GPx4 (Figure 5). Inhibitors of system Xc− such as erastin, sulfasalazine, and sorafenib are class 1 ferroptosis inducing compounds (FIN I). In contrast, inhibitors of GPx4, such as Ras selective lethal 3 (RSL3), are class 2 ferroptosis inducing compounds (FIN II).
Blocking system Xc− is a well-known mechanism to provoke ferroptosis [66]. To that purpose, different strategies are reported in the literature, such as glutamate excess, the glutaminolysis pathway [85], and system Xc− direct inhibition by erastin. Erastin is a well-known inhibitor of system Xc− decreasing the intracellular concentration of cystine [86]. Erastin-induced ferroptosis can also promote endoplasmic reticulum stress [56]. Erastin was initially described as a cancer cell killer via a pathway different from apoptosis [18], which was more recently identified as ferroptosis [5]. Indeed, erastin has been shown to enhance cell sensitivity to chemotherapy in lung cancer, rhabdomyosarcoma, and glioblastoma models [86,87,88] and to alleviate cell resistance to chemotherapeutic drugs in head, neck, and ovarian cancer cells [89,90]. Erastin is also a radiosensitizer in radiotherapy [91,92,93]. However, erastin is rarely tested in vivo because of its poor water solubility. Piperazine-erastin (PE) and imidazole ketone erastin (IKE) are water-soluble erastin-based compounds. PE was shown to decrease tumor cell growth in mice, and IKE induced ferroptosis in a B cell lymphoma model [94,95]. Sulfasalazine and sorafenib are pharmacological reagents that induce ferroptosis in several cancer types by inactivating system Xc− [66,96,97,98,99,100,101]. However, erastin has a higher inhibitory effect on system Xc− than the two other molecules, sulfasalazine and sorafenib [66]. Other strategies, such as engineered “cyst(e)inase”, which degrades cell cystine required for GSH production, showed similar results on lymphatic leukemia with the system Xc− blocking strategy [102]. GSH synthesis can also be inhibited by buthionine sulfoximine by inactivating 𝛾-glutamylcysteine synthase.
The second target to induce ferroptosis is GPx4. RSL3, a FIN II, reduces GPx4 catalytic activity and thus drives cells to ferroptosis [103] in colorectal cancer, for example [104]. On the contrary, RSL3-driven ferroptosis can be reversed by GPx4 overexpression [96]. Withaferin A and Altretamine also belong to FIN II and induce ferroptosis in neuroblastoma and ovarian cells, respectively [105,106]. Other compounds, such as ML-210 (DPI10) and ML-162 (DPI7), are also classified as FIN II [107,108]. FIN56 is a ferroptosis-inducer classified in class 3 ferroptosis inducers, although it promotes the degradation of GPx4 through a not yet fully described mechanism [109] that is potentiated by statins [72]. FIN56 also binds and activates squalene synthase leading to the depletion of the lipophilic antioxidant coenzyme Q10. Finally, FINO2, an endoperoxide-containing 1,2-dioxolane, indirectly inactivates GPx4 through a yet unknown pathway. Moreover, FINO2 can react with Fe2+ to produce radicals and aid in lipid peroxidation [110]. Besides inhibitors of Xc− and of GPx4, ferroptosis can also be initiated by increasing the labile iron pool (LIP) through the excessive expression of transferrin, limited expression of ferritin, or activation of heme-oxygenase [105,111,112].
5.2. Ferroptosis Inhibitors
Following the research around ferroptosis mechanisms, specific ferroptosis inhibitors such as metal-chelators such as deferoxamine (DFO) and deferiprone, and lipophilic antioxidants such as ferrostatin-1 (Fer-1), liproxstatin-1 (Lip-1), and vitamin E (⍺-tocopherol) have been discovered (Figure 5).
DFO (Figure 6A) is a metal-chelating agent for trivalent cations such as ferric and aluminum ions. The affinity constants of complex formation are very high, 1031 M−1 and 1025 M−1, respectively, and are carried out on a 1:1 molar basis. DFO is able to bind free iron in plasma or cells to form the ferrioxamine complex. It can also chelate iron bound to ferritin but cannot chelate iron in hemoglobin. As a result, DFO promotes the excretion of iron and aluminum in urine and feces, thereby reducing their pathological effects in organs. Interestingly, iron and aluminum overload can be screened by the DFO test. This test is based on the fact that DFO does not increase the excretion of iron and aluminum above a certain threshold in healthy subjects. DFO is prescribed for patients suffering from primary hemochromatosis (extra iron builds up in the body to harmful levels caused by gene disorders), which is not curable by phlebotomy, secondary hemochromatosis (extra iron builds up in the body to harmful levels caused by another disease), and renal aluminum poisoning. It can be administered either subcutaneously, intravenously by infusion, intramuscularly, or intraperitoneally. DFO has shown interesting results in ferroptosis-based studies. For example, spinal cord injury in mice was treated by DFO decreased iron concentration and promoted the expression of GPx4, system Xc−, and GSH [113]. DFO is also reported to preserve neurons in the early stages of Parkinson’s disease [114] and to reduce ROS formation in breast cancer cells and corneal epithelial cells driven to ferroptosis [115,116]. Deferiprone (Figure 6B) is a bidentate ligand that binds to iron in a molar ratio of 3:1.
Unlike DFO, deferiprone is a membrane-permeant molecule. Deferiprone promotes iron excretion in transfusion-dependent β-thalassemia. This drug is administered orally and prescribed as a monotherapy to treat iron overload when current chelation therapy is unsuitable or in combination with another chelating drug (mainly DFO) when the monotherapy is ineffective or in the case of life-threatening iron overload. To date, deferiprone has never been tested on a ferroptosis model, although it presents similar properties as DFO. For example, it was shown to reduce intracellular iron levels and inhibit lipid peroxidation in hepatocytes [117]. Deferiprone was also able to chelate iron deposits in the red blood cells of patients with thalassemia and alleviate plasma membrane dysfunction.
Ferrostatin 1 (Fer-1; Figure 6C) is a ferroptosis inhibitor that prevents lipid peroxidation by scavenging lipid alkoxyl radicals [118]. Dixon et al. were the first to identify its rescuing effect on glutamate-induced ferroptosis in rat brains [5]. This molecule was also able to restore mitochondrial function in ferroptosis-based neuronal cell models and prevent their death [119]. Furthermore, Fer-1 showed antioxidant effects in cell models of Huntington’s disease, kidney dysfunction, atherosclerosis, and lung cancer by reducing oxidation of lipids and ROS production, and it indirectly promoted the expression of GPx4 [12,14,120]. These later findings suggest that ferroptosis is a key event in the progression of these diseases. Lipophilic antioxidants such as Lip-1 and vitamin E also showed anti-ferroptosis effects. To date, the Lip-1 mode of action is not well explained in the literature, but it is believed to have the same scavenging activity as Fer-1 due to the presence of two amine groups in its structure (Figure 6D) [121]. Furthermore, Lip-1 was able to inhibit ferroptosis in mice fibroblasts where GPx4 was knocked-out [58]. Vitamin E—the lipid-soluble form of ⍺-tocopherol that blocks oxidation chain reaction in the membrane—is less efficient than Fer-1 and Lip-1 [6,122]. Vitamin E suppressed FIN56-induced ferroptosis in fibrosarcoma cells and prevented lipid peroxidation-induced cell death in acute liver failure [110,123].
Ferroptosis inducers and inhibitors have represented a breakthrough in understanding this cell-death mechanism. They have also set up the basis to discover other ferroptosis regulatory molecules.
6. Ferroptosis in Cardiovascular and Neurodegenerative Diseases
Atherosclerosis is a cardiovascular disease characterized by the formation of plaques at the artery’s wall, narrowing the blood flow passage. In the context of inflammation and oxidative stress, atherosclerosis starts with an endothelial dysfunction associated with low-density lipoproteins (LDL) entry and oxidation in the sub-endothelium. Macrophages at that site phagocyte oxidized LDL and became foam cells appearing as a fatty streak [118]. Although the entire mechanism leading to atherosclerosis has not yet been clarified, several studies have provided a reliable correlation between ferroptosis markers and atherosclerosis (Figure 7). Oxidized phospholipids and iron overload are master players in ferroptosis [124] and are well-known for their role in the context of oxidative stress leading to atherosclerosis [119,125,126]. Foam cells of atherosclerotic plaques are found to be overloaded in transferrin-receptor proteins, one of the endogenous ferroptosis inducers [127]. Moreover, Vinchi et al., showed that non-transferrin-bound iron had provoked pro-atherosclerotic responses in mice, such as endothelial permeabilization and activation, elevated oxidized LDL, macrophage recruitment, plaque formation, and death of vascular cells [128]. Iron overload and lipid peroxidation in macrophages has been attributed in many studies to their accumulation, pro-inflammatory response, and death in the atherosclerosis plaque [129,130,131,132]. In the same context, LOX overexpression—a cell ferroptosis inducer—also leads to atherosclerosis [124]. In a recent study, Sampilvanjil et al. induced ferroptosis in vascular smooth muscle cells with tobacco smoking [133], known as a key factor for the development of atherosclerosis [134]. GPx4, a ferroptosis-resistant enzyme, plays a major role in the development of atherosclerosis. Overexpression of Gpx4 reduced atherosclerotic lesions in mice, as discussed by Guo et al. [135]. Early studies showed that selenium supplementation, a co-factor for GPx4 activity, can stop the development of atherosclerosis plaques and reduce lesions in animal models [136,137,138]. Furthermore, ferroptosis inhibitors, such as Fer-1, DFO, and vitamin E, can prevent atherosclerosis [139,140]. Indeed, Bai et al. showed that Fer-1 inhibits lipid peroxidation and iron accumulation and induces GPx4 overexpression as well as GSH production in an atherosclerosis mice model [12]. DFO, on the other hand, has been shown to reduce atherosclerotic inflammation and lesions, even before the discovery of ferroptosis [141]. Wang and Tang inhibited endothelial cell ferroptosis using Fer-1 and DFO [142]. Other cardiovascular diseases, such as cardiomyopathy and cardiac dysfunction, are also induced by iron overload [143,144]. Indeed, cardiomyopathy appears in cancer patients treated with doxorubicin due to its ability to accumulate iron and thus induce ferroptosis [145]. According to some studies, ferroptosis is a leading cause of myocardial I/R injury (tissue damage caused by the return of blood supply after a period of lack of oxygen) whose damage can be reduced by Fer-1 and DFO [85,146,147]. Lip-1 was able to regulate mitochondrial ROS and restore GPx4 levels in the heart of the I/R injury mouse model [148]. Fer-1 was shown to inhibit cell death and restore redox balance in a cell model of ischemic heart disease induced by H2O2 [149]. A study suggested that prior treatment with Fer-1 before heart transplantation surgeries would avoid graft dysfunctions [146]. Other cardiovascular conditions, such as heart failure, vascular injury, and strokes, were reviewed with their ferroptosis biomarkers [150].
Several scientific data support the relationship between ferroptosis and other chronic diseases, such as Huntington’s, a genetic neurodegenerative disease. Biomarkers of this disease, including excessive iron metabolism, glutamate toxicity, dysregulation in GSH-mediated redox potential and lipid peroxidation, are also markers of ferroptosis [151,152,153]. DFO and Fer-1 protected the death of neurons in Huntington models [14,154]. In addition, Alzheimer’s disease and Parkinson’s disease are also common neurodegenerative diseases associated with loss of memory and automaticity, respectively. Several features of these diseases’ physiopathology are consistent with ferroptosis pathways (Figure 7). Long before the term ferroptosis appeared, scientists observed increased iron levels in the substantia nigra region of Parkinson’s disease brains [19,155,156,157], causing elevated lipid peroxides and oxygen free radicals [158,159,160,161]. The loss of nigral cells due to oxidative damage is a major characteristic of this disease’s severity [162]. In Alzheimer’s disease, alterations in iron levels and iron regulatory proteins (ferritin and transferrin) associated with lipid peroxidation and oxidative stress were observed in the hippocampus [23,163,164,165,166,167,168]. Nowadays, ferroptosis has been introduced as a key player in the progression of many neurodegenerative diseases [169,170,171]. Low expressions of antioxidant machinery proteins, including GPx4, GSH, system Xc−, and CoQ10, and mitochondrial dysfunctions, were also reported in the degenerative neurons [172,173,174,175,176,177]. Ferritinophagy is also a ferroptosis process implicated in specific neurotoxicities [178]. In addition, antioxidant therapies using ferroptosis inhibitors (Fer-1, Lip-1, DFr, and DFO) and targeting pathological properties of neurodegenerative diseases have achieved promising results on cellular and animal models [14,114,179,180]. Dietary supplementations with the antioxidant CoQ10 have also been discussed as a potential neuroprotective candidate [181].
Interestingly, iron chelation therapy for neurodegenerative diseases has recently been featured in several clinical trials. Early-stage Parkinson’s disease patients were administered different doses of DFr for 6 months in an independent phase 2 double-blind, placebo-controlled randomized trial [15]. As a blood–brain barrier permeable iron chelator, DFr was well tolerated by the patients in this trial but had a non-significant trend to reduce iron content and improve quality of life [182]. Similarly, DFr was tested in a large phase 3, European multicentric, parallel-group, placebo-controlled randomized trial for Parkinson’s disease patients, but results are not yet published [183,184]. This iron-chelating drug was also evaluated in a multicenter, unblinded, single-arm pilot trial on patients with cerebral iron overloads (clinical symptoms: strong disability and reduction of autonomy) [185]. This trial documented a reduction in iron accumulations and improvements in the motor activities of patients [186]. In France, there is now a promising, still active, double-blind, placebo-controlled randomized study for DFr on patients with amyotrophic lateral sclerosis (a neurodegenerative disease that affects the brain and spinal cord) and causes loss of muscle control [187].
The discovery of ferroptosis has led to a better understanding of various diseases, and even though it is not yet mentioned in clinical studies, its inducers and inhibitors highlight a promising future for disease treatments.
7. Ferroptosis Modulation Inspired by Nature
7.1. Natural Compounds
For many years, the drug development industry has relied on natural products to treat and prevent various diseases. Bioactive molecules extracted from natural resources have been proven to possess anti-cancer, anti-inflammatory, antibacterial, immunomodulatory, and antioxidant activities. However, to date, only a few published studies directly correlate the effect of natural compounds on the regulation of iron metabolism, lipid peroxidation, GPx4 activity, and other pathways linked to ferroptosis induction or inhibition.
In 2015, Tu Youyou shared the Nobel Prize in Medicine for her discovery of artemisinin from the plant Artemisia annua as an antimalaria drug, which turned out to be a promising drug for various other diseases, including cancer. Further studies showed that artemisinin and its derivatives could stimulate ferroptosis cell pathways, including the downregulation of GPx4 expression, increasing the production of ROS and intracellular iron. Other natural-based compounds have been defined as ferroptosis inducers, such as Ferroptocide and Erianin. Ferroptocide, a stereochemical derivative of a fungi metabolite called “Pleuromutilin”, can induce ferroptosis in breast cancer cells by inactivating the thioredoxin, a cell antioxidant enzyme [188]. Chen et al. demonstrated that Erianin, a natural product isolated from Dendrobium chrysotoxum Lindl, induced ferroptosis in lung cancer cells where ROS accumulation, lipid peroxidation, and GSH depletion were observed [189].
Certain bioactive natural compounds, such as Ruscogenin and Curcumin, may exert ferroptosis regulatory activities. While these compounds were shown to induce ferroptosis for cancer treatments, they can also act as ferroptosis inhibitors for tissue injury treatments. However, Ruscogenin is an important steroid sapogenin derived from Ophiopogon japonicus. In pancreatic cancer cells, it increased intracellular ferrous ions as well as ROS production [190]. While in myocardial injury and acute kidney injury mice models, this compound has led to the upregulation of GPx4 expression, an increase in GSH concentration, and a decrease of intracellular iron and lipid peroxidation in a dose-dependent manner [191,192]. Curcumin from Curcuma longa has stimulated cell death by ferroptosis via accumulating iron ions in breast cancer cells and sabotaging GPx4 activity in glioblastoma cells [193,194]. On the contrary, Curcumin triggered the antioxidant defense mechanism against induced ferroptosis in renal tubular cells and thus decreased lipid peroxidation [195]. This controversiality requires more studies that underline the biochemical and/or cellular conditions that regulate these compounds’ mode of action.
Treating ferroptosis-induced diseases with natural bioactive compounds has also been investigated. Flavonoids such as Baicalein, Kaempferol, and Quercetin have long been known for their antioxidant properties in cardiovascular and neurodegenerative diseases. Baicalein, derived from the root of Scutellaria baicalensis, has been served as a food supplement in many countries [196]. In 2009, Perez and his colleagues demonstrated that this compound protects against the cellular Fenton reaction by chelating ferrous ions [197]. In a recent study in a posttraumatic epilepsy rat model, Baicalein revealed its neuroprotective effects by decreasing the production of lipid peroxides [198]. Kaempferol is found in diverse foods, including broccoli, peaches, spinach, and green tea [199]. Yuan et al. showed that this antioxidant compound can deattenuate neuronal ferroptosis by enhancing the Xc−/GPx4 signaling pathway, thus reducing lipid peroxidation [200]. Quercetin is also consumed via a wide variety of fruits, vegetables, and beans. It inhibited erastin-induced ferroptosis in bone marrow-derived mesenchymal stem cells via several antioxidant pathways, including lipid peroxide scavenging [201].
Although this review highlights a few examples of natural compounds that regulate ferroptosis, dozens of others are reported in the literature. Zhang et al., and Zheng et al., nicely reviewed the ferroptosis regulatory activity of natural compounds [11,202].
7.2. Bioactive Peptides
Bioactive peptides are short sequences (2 to 40 units) of characteristic amino acids initially encrypted inside the 3-dimensional structure of proteins. Although these peptides are widely reported for their antioxidant activities, such as radical scavenging, reducing power, and metal chelation, to date, there is no study investigating them in a ferroptosis model. Therefore, in this part, we will review the antioxidant properties of bioactive peptides such as metal chelation, reduction of lipid peroxidation, modulation of GSH content, and GPx activity that might confer their interest for anti-ferroptotic properties. These peptides can be found, synthesized, and/or produced by bacteria, plants, animals, and humans. For example, carnosine is a bioactive dipeptide produced in the liver from beta-alanine and histidine and has ROS-scavenging power, a known anti-ferroptosis pathway [203].
Moreover, GSH, the important ferroptosis cell regulator, is a bioactive tripeptide with a variety of antioxidant properties thanks to its special amino acid sequence (γ-l-glutamyl-l-cysteinylglycine) [82]. Since the antioxidant defense mechanism of human beings is not enough to fight against all the oxidative stress that we encounter in our lives, the discovery and extraction of external bioactive peptides are essential. These peptides can be produced in a variety of ways, including enzymatic hydrolysis of proteins, microbial fermentation, and chemical synthesis. Depending on the protein source, the production technique used, the processing condition, and the post-production treatments, peptide sequences, and their bioactive properties can vary. Nowadays, researchers race towards better-producing antioxidant peptides, most of which have promising inhibitory effects on ferroptosis.
Biochemical tests of bioactive peptides (whether in a mixture like peptide hydrolysates or pure) are the most common evaluation procedures used among researchers due to their easy operation, high efficiency, low toxicity, good reproducibility, and short experimental period. Evaluation methods based on metal ion chelating activity and radical scavenging power can be indicators for peptide anti-ferroptosis activity. Examples of these methods are DPPH and ABTS radical scavenging, the FRAP method, and the ORAC assay. In addition, the inhibition of lipid peroxidation has been screened using the TBARS method on a liposome peroxidation model [204]. Researchers have widely explored antioxidant peptides from different plant and animal origins (Table 1). The presence of amino acids, such as tyrosine (Y), tryptophan (W), methionine (M), lysine (K), proline (P), cystine (C), histidine (H), valine (V), leucine (L), and alanine (A), would be ascribed to different antioxidant activities possessed by these peptides [205]. For example, aromatic amino acids can donate protons to electron-deficient radicals, thus improving the radical scavenging capacity of peptides; also, histidine can donate hydrogen atoms, tap lipid peroxyl radicals, and/or chelate metal ions via its imidazole group, which traps lipid peroxyl radicals. The position of the amino acids inside the primary peptide sequence also plays a major role in the overall antioxidant capacity. Thus, histidine at the C terminus acts mainly as a scavenger of various radicals and at the N terminus as a metal ion chelator [206]. Chemical synthesis of metal-chelating and ROS-scavenging peptides have succeeded as well. For example, ref. [207] showed that the synthesized peptide sequences FDDDK and FEEEK acquire both iron (III)-chelating activity and HO. radical scavenging activity by spectrophotometric assays.
Table 1.
Origin | Peptide Sequences | Antioxidant Activities | References |
---|---|---|---|
Soy proteins | VNPESQQGSPR; LLPHH; LLPLPVLK; WLR; MLPVMR; SWLRL; SGDAL; SHECN; LPFAM | ABTS, DPPH, and Hydroxyl radical scavenging activities; Ferric reducing power; Inhibition of Fenton reaction | [208,209,210,211,212] |
Rice proteins | FRDEHKK; RPNYTDA; TSQLLSDQ; TRTGDPFF; NFHPQ | ABTS, DPPH, and Hydroxyl radical scavenging activities; Lipid peroxidation inhibition in liposome model; Ferric reducing power | [141,208] |
Cereal proteins (wheat, corn, pearl millet, barley) | KVALMSAGSMH; AGLPM; HALGA; SDRDLLGPNNQYLP; SVNVPL | Oxygen radical absorbance capacity; DPPH and Hydroxyl radical scavenging activities, Lipid peroxidation inhibition in liposome model; Iron (II) chelating activity | [206,209,210,211] |
Seed proteins (rapeseed, walnuts, pine nut) |
PAGPF; ADAF; KWFCT; QWFCT | DPPH radical scavenging activities; Lipid peroxidation inhibition in liposome model; Iron (II) chelating activity, Ferric reducing power | [212,213,214] |
Egg proteins | WNIP; GWNI; WYGPD; KLSDW; KGLWE; IRW | Oxygen radical absorbance capacity; DPPH radical scavenging activity; Lipid peroxidation inhibition in liposome model | [215,216,217] |
Fish proteins | VPKNYFHDIV; LVMFLDNQHRVIRH; FVNQPYLLYSVHMK; SCH; GVSGLHID; MTTL; LEW; YYPYQL; LEW; MTTL; YYPYQL | Oxygen radical absorbance capacity; ABTS and DDPH radical scavenging activities; Iron (II) chelating activity | [218,219,220,221] |
Beef proteins | SNAAC; SAGNPN; DLEE; FWIIE; APYMM; GKFNV | Oxygen radical absorbance capacity; ABTS, DDPH, Hydroxyl, and Superoxide anion radical scavenging activities; Lipid peroxidation inhibition in liposome model; inhibition of Fenton’s reagent-induced protein oxidation; Iron (II) chelating activity | [222,223,224,225] |
Peptides can also be evaluated via in vitro biological assays. Various cell-based oxidative stress models have been employed to investigate the antioxidant activity of peptides obtained from natural sources. Evaluation of these peptides mainly occurs by following up biomarkers such as cell viability, GSH, ROS production, lipid peroxidation, and antioxidant enzymes (SOD, CAT, and GPx) activities which are, as recently defined, biomarkers for ferroptosis regulation. The IYVVDLR, IYVFVR, VVFVDRL, and VIYVVDLR peptides from soybean hydrolysates were able to reduce lipid peroxidation and ROS production as well as increase cell viability and GSH content in H2O2-treated Caco2 cells [226]. In H2O2-treated HepG2 cells, the RDPEER peptide from watermelon seed protein hydrolysates and EDIVCW, MEPVW, and YWDAW peptides from Monkfish hydrolysates inhibited the production of lipid peroxides and other cells ROS [227,228]. Wang et al. determined that peptides DSTRTQ, DVYSF, and ESKPV can reduce ROS content in vascular smooth muscle cells [229]. The PHP peptide from Chinese Baijiu has decreased ROS and lipid peroxide content and elevated GSH concentration and antioxidant enzyme activities in 2,2′-azobis (2-methyl-propanimidamidine) dihydrochloride (AAPH)-treated HepG2 cells [230]. A more scientific basis is still required to determine the exact mechanisms of these peptides at the cell level.
As for in vivo evaluations, very few studies have reported the antioxidant activity of bioactive peptides on animal models. In diabetic mice, Jiang et al. identified that antioxidant peptides from red deer antlers could reduce malondialdehyde levels [231]. Ben Khaled et al. showed that sardine protein hydrolysates were able to reduce lipid peroxidation and enhance the activity of SOD and GPx in rats fed with a cholesterol-enriched diet [232]. Wheat bran protein hydrolysate had oxygen radical absorbance capacity in hypersensitive rats [233]. Finally, Ding et al. observed lower serum MDA levels in mice treated with jellyfish protein hydrolysates compared to non-treated mice [234]. Although experimenting on animal models is time-consuming and very sensitive, it provides a closer insight into the functionality of the organism. Yet tremendous scientific efforts are still required to determine the bioavailability, toxicity, required dose, and side effects of the various antioxidant peptides known to date.
8. Conclusions
In summary, the discovery of ferroptosis was a huge scientific progress in the biological domain. First, mainly used as a tool to kill cancer cells, ferroptosis was then discovered as implicated in cardiovascular and neurodegenerative diseases. Finally, the great value of identifying ferroptosis inducers and inhibitors was translated into disease-treatment studies. However, to date, ferroptosis has not been reported in any clinical trials (www.clinicaltrials.gov (accessed on 25 January 2022)). Therefore, more in-depth studies are required to make connections between cell/animal-based data and the complexity of the human organism. The main problem might be the lack of cell-based ferroptosis models related to those diseases to evaluate ferroptosis inhibitors. Nevertheless, scientists have also addressed people’s need to consume natural products by studying multiple different natural compounds on ferroptosis regulation. Although bioactive peptides have not been directly linked to ferroptosis regulation, their acquired various antioxidant activities, such as iron chelation properties, modulation of ferroptosis biomarkers, and restoration of redox homeostasis, might open a new area for the evaluation of those natural sources of ferroptosis-related conditions.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
No new data were created.
Conflicts of Interest
The authors declare no conflict of interest.
Funding Statement
The authors acknowledge financial support from the “Impact Biomolecules” project of the “Lorraine Université d’Excellence” (in the context of the “Investissements d’avenir” program implemented by the French National Research Agency—ANR project number 15-004). The authors would also like to thank the financial support of ANR JCJC MELISSA (2020).
Footnotes
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
References
- 1.Blaustein R. The Great Oxidation Event. BioScience. 2016;66:189–195. doi: 10.1093/biosci/biv193. [DOI] [Google Scholar]
- 2.Carter R. Oxygen: The Molecule That Made the World. J. R. Soc. Med. 2003;96:46–47. doi: 10.1258/jrsm.96.1.46. [DOI] [Google Scholar]
- 3.Fischer W.W., Hemp J., Valentine J.S. How Did Life Survive Earth’s Great Oxygenation? Curr. Opin. Chem. Biol. 2016;31:166–178. doi: 10.1016/j.cbpa.2016.03.013. [DOI] [PubMed] [Google Scholar]
- 4.Benzie I.F.F. Evolution of Antioxidant Defence Mechanisms. Eur. J. Nutr. 2000;39:53–61. doi: 10.1007/s003940070030. [DOI] [PubMed] [Google Scholar]
- 5.Dixon S.J., Lemberg K.M., Lamprecht M.R., Skouta R., Zaitsev E.M., Gleason C.E., Patel D.N., Bauer A.J., Cantley A.M., Yang W.S., et al. Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death. Cell. 2012;149:1060–1072. doi: 10.1016/j.cell.2012.03.042. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Sun Y., Chen P., Zhai B., Zhang M., Xiang Y., Fang J., Xu S., Gao Y., Chen X., Sui X., et al. The Emerging Role of Ferroptosis in Inflammation. Biomed. Pharmacother. 2020;127:110108. doi: 10.1016/j.biopha.2020.110108. [DOI] [PubMed] [Google Scholar]
- 7.Valashedi M.R., Najafi-Ghalehlou N., Nikoo A., Bamshad C., Tomita K., Kuwahara Y., Sato T., Roushandeh A.M., Roudkenar M.H. Cashing in on Ferroptosis against Tumor Cells: Usher in the next Chapter. Life Sci. 2021;285:119958. doi: 10.1016/j.lfs.2021.119958. [DOI] [PubMed] [Google Scholar]
- 8.Liang C., Zhang X., Yang M., Dong X. Recent Progress in Ferroptosis Inducers for Cancer Therapy. Adv. Mater. Deerfield Beach Fla. 2019;31:e1904197. doi: 10.1002/adma.201904197. [DOI] [PubMed] [Google Scholar]
- 9.Nimse S.B., Pal D. Free Radicals, Natural Antioxidants, and Their Reaction Mechanisms. RSC Adv. 2015;5:27986–28006. doi: 10.1039/C4RA13315C. [DOI] [Google Scholar]
- 10.Elias R.J., Kellerby S.S., Decker E.A. Antioxidant Activity of Proteins and Peptides. Crit. Rev. Food Sci. Nutr. 2008;48:430–441. doi: 10.1080/10408390701425615. [DOI] [PubMed] [Google Scholar]
- 11.Zhang S., Hu R., Geng Y., Chen K., Wang L., Imam M.U. The Regulatory Effects and the Signaling Pathways of Natural Bioactive Compounds on Ferroptosis. Foods. 2021;10:2952. doi: 10.3390/foods10122952. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Bai T., Li M., Liu Y., Qiao Z., Wang Z. Inhibition of Ferroptosis Alleviates Atherosclerosis through Attenuating Lipid Peroxidation and Endothelial Dysfunction in Mouse Aortic Endothelial Cell. Free Radic. Biol. Med. 2020;160:92–102. doi: 10.1016/j.freeradbiomed.2020.07.026. [DOI] [PubMed] [Google Scholar]
- 13.Fuhrmann D.C., Mondorf A., Beifuß J., Jung M., Brüne B. Hypoxia Inhibits Ferritinophagy, Increases Mitochondrial Ferritin, and Protects from Ferroptosis. Redox Biol. 2020;36:101670. doi: 10.1016/j.redox.2020.101670. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Skouta R., Dixon S.J., Wang J., Dunn D.E., Orman M., Shimada K., Rosenberg P.A., Lo D.C., Weinberg J.M., Linkermann A., et al. Ferrostatins Inhibit Oxidative Lipid Damage and Cell Death in Diverse Disease Models. J. Am. Chem. Soc. 2014;136:4551–4556. doi: 10.1021/ja411006a. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Imperial College London . A Pilot Clinical Trial With the Iron Chelator Deferiprone in Parkinson’s Disease. Clinicaltrials.gov; London, UK: 2020. [Google Scholar]
- 16.Seiler A., Schneider M., Förster H., Roth S., Wirth E.K., Culmsee C., Plesnila N., Kremmer E., Rådmark O., Wurst W., et al. Glutathione Peroxidase 4 Senses and Translates Oxidative Stress into 12/15-Lipoxygenase Dependent- and AIF-Mediated Cell Death. Cell Metab. 2008;8:237–248. doi: 10.1016/j.cmet.2008.07.005. [DOI] [PubMed] [Google Scholar]
- 17.Yang A., Stockwell B.R. Synthetic Lethal Screening Identifies Compounds Activating Iron-Dependent, Nonapoptotic Cell Death in Oncogenic-RAS-Harboring Cancer Cells. Chem. Biol. 2008;15:234–245. doi: 10.1016/j.chembiol.2008.02.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Dolma S., Lessnick S.L., Hahn W.C., Stockwell B.R. Identification of Genotype-Selective Antitumor Agents Using Synthetic Lethal Chemical Screening in Engineered Human Tumor Cells. Cancer Cell. 2003;3:285–296. doi: 10.1016/S1535-6108(03)00050-3. [DOI] [PubMed] [Google Scholar]
- 19.Sofic E., Riederer P., Heinsen H., Beckmann H., Reynolds G.P., Hebenstreit G., Youdim M.B. Increased Iron (III) and Total Iron Content in Post Mortem Substantia Nigra of Parkinsonian Brain. J. Neural Transm. 1988;74:199–205. doi: 10.1007/BF01244786. [DOI] [PubMed] [Google Scholar]
- 20.Bannai S. Exchange of Cystine and Glutamate across Plasma Membrane of Human Fibroblasts. J. Biol. Chem. 1986;261:2256–2263. doi: 10.1016/S0021-9258(17)35926-4. [DOI] [PubMed] [Google Scholar]
- 21.Ursini F., Maiorino M. Lipid Peroxidation and Ferroptosis: The Role of GSH and GPx4. Free Radic. Biol. Med. 2020;152:175–185. doi: 10.1016/j.freeradbiomed.2020.02.027. [DOI] [PubMed] [Google Scholar]
- 22.Hochstein P., Ernster L. ADP-Activated Lipid Peroxidation Coupled to the TPNH Oxidase System of Microsomes. Biochem. Biophys. Res. Commun. 1963;12:388–394. doi: 10.1016/0006-291X(63)90111-6. [DOI] [PubMed] [Google Scholar]
- 23.Hallgren B., Sourander P. The Non-Haemin Iron in the Cerebral Cortex in Alzheimer’s Disease. J. Neurochem. 1960;5:307–310. doi: 10.1111/j.1471-4159.1960.tb13369.x. [DOI] [PubMed] [Google Scholar]
- 24.Filer L.J., Rumery R., Mason K. Specific Unsaturated Fatty Acids in the Production of Acid Fast Pigment in the Vitamine E Deficient Rat and the Protective Action of Tocopherols; Proceedings of the Transactions of the First Conference on Biological Antioxidants; New York, NY, USA. 10–11 October 1946. [Google Scholar]
- 25.Braconnot H. Mémoire Sur La Nature Des Corps Gras. Anna. Chim. 1815;93:225–277. [Google Scholar]
- 26.Abbaspour N., Hurrell R., Kelishadi R. Review on Iron and Its Importance for Human Health. J. Res. Med. Sci. Off. J. Isfahan Univ. Med. Sci. 2014;19:164–174. [PMC free article] [PubMed] [Google Scholar]
- 27.Yiannikourides A., Latunde-Dada G.O. A Short Review of Iron Metabolism and Pathophysiology of Iron Disorders. Medicines. 2019;6:85. doi: 10.3390/medicines6030085. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Ems T., St Lucia K., Huecker M.R. StatPearls. StatPearls Publishing; Treasure Island, FL, USA: 2021. Biochemistry, Iron Absorption. [PubMed] [Google Scholar]
- 29.Knutson M.D. Iron Transport Proteins: Gateways of Cellular and Systemic Iron Homeostasis. J. Biol. Chem. 2017;292:12735–12743. doi: 10.1074/jbc.R117.786632. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Andrews N.C., Schmidt P.J. Iron Homeostasis. Annu. Rev. Physiol. 2007;69:69–85. doi: 10.1146/annurev.physiol.69.031905.164337. [DOI] [PubMed] [Google Scholar]
- 31.Minotti G., Aust S.D. The Role of Iron in the Initiation of Lipid Peroxidation. Chem. Phys. Lipids. 1987;44:191–208. doi: 10.1016/0009-3084(87)90050-8. [DOI] [PubMed] [Google Scholar]
- 32.Fenton H.J.H. LXXIII.—Oxidation of Tartaric Acid in Presence of Iron. J. Chem. Soc. Trans. 1894;65:899–910. doi: 10.1039/CT8946500899. [DOI] [Google Scholar]
- 33.Yaman S.O., Ayhanci A. Lipid Peroxidation. Intech Open; Rijeka, Croatia: 2021. [Google Scholar]
- 34.Ayala A., Muñoz M.F., Argüelles S. Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal. Oxid. Med. Cell. Longev. 2014;2014:e360438. doi: 10.1155/2014/360438. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Yin H., Xu L., Porter N.A. Free Radical Lipid Peroxidation: Mechanisms and Analysis. Chem. Rev. 2011;111:5944–5972. doi: 10.1021/cr200084z. [DOI] [PubMed] [Google Scholar]
- 36.Guéraud F., Atalay M., Bresgen N., Cipak A., Eckl P.M., Huc L., Jouanin I., Siems W., Uchida K. Chemistry and Biochemistry of Lipid Peroxidation Products. Free Radic. Res. 2010;44:1098–1124. doi: 10.3109/10715762.2010.498477. [DOI] [PubMed] [Google Scholar]
- 37.Negre-Salvayre A., Auge N., Ayala V., Basaga H., Boada J., Brenke R., Chapple S., Cohen G., Feher J., Grune T., et al. Pathological Aspects of Lipid Peroxidation. Free Radic. Res. 2010;44:1125–1171. doi: 10.3109/10715762.2010.498478. [DOI] [PubMed] [Google Scholar]
- 38.Vaca C.E., Wilhelm J., Harms-Ringdahl M. Interaction of Lipid Peroxidation Products with DNA. A Review. Mutat. Res. Genet. Toxicol. 1988;195:137–149. doi: 10.1016/0165-1110(88)90022-X. [DOI] [PubMed] [Google Scholar]
- 39.Benzie I.F.F. Lipid Peroxidation: A Review of Causes, Consequences, Measurement and Dietary Influences. Int. J. Food Sci. Nutr. 1996;47:233–261. doi: 10.3109/09637489609012586. [DOI] [PubMed] [Google Scholar]
- 40.Natto C., Kawamura M., Yamamoto Y. Lipid Peroxides as the Initiating Factor of Atherosclerosis. Ann. N. Y. Acad. Sci. 1993;676:27–45. doi: 10.1111/j.1749-6632.1993.tb38723.x. [DOI] [PubMed] [Google Scholar]
- 41.Nilsson J., Regnström J., Frostegård J., Stiko A. Lipid Oxidation and Atherosclerosis. Herz. 1992;17:263–269. [PubMed] [Google Scholar]
- 42.Galluzzi L., Vitale I., Abrams J.M., Alnemri E.S., Baehrecke E.H., Blagosklonny M.V., Dawson T.M., Dawson V.L., El-Deiry W.S., Fulda S., et al. Molecular Definitions of Cell Death Subroutines: Recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ. 2012;19:107–120. doi: 10.1038/cdd.2011.96. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Kerr J.F.R., Wyllie A.H., Currie A.R. Apoptosis: A Basic Biological Phenomenon with Wide-Ranging Implications in Tissue Kinetics. Br. J. Cancer. 1972;26:239–257. doi: 10.1038/bjc.1972.33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Alberts B., editor. Molecular Biology of the Cell. 5th ed. Garland Science; New York, NY, USA: 2008. [Google Scholar]
- 45.Raychaudhuri S. A Minimal Model of Signaling Network Elucidates Cell-to-Cell Stochastic Variability in Apoptosis. PLoS ONE. 2010;5:e11930. doi: 10.1371/journal.pone.0011930. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Tixeira R., Caruso S., Paone S., Baxter A.A., Atkin-Smith G.K., Hulett M.D., Poon I.K.H. Defining the Morphologic Features and Products of Cell Disassembly during Apoptosis. Apoptosis Int. J. Program. Cell Death. 2017;22:475–477. doi: 10.1007/s10495-017-1345-7. [DOI] [PubMed] [Google Scholar]
- 47.deCathelineau A.M., Henson P.M. The Final Step in Programmed Cell Death: Phagocytes Carry Apoptotic Cells to the Grave. Essays Biochem. 2003;39:105–117. doi: 10.1042/bse0390105. [DOI] [PubMed] [Google Scholar]
- 48.Raffray M., Cohen G.M. Apoptosis and Necrosis in Toxicology: A Continuum or Distinct Modes of Cell Death? Pharmacol. Ther. 1997;75:153–177. doi: 10.1016/S0163-7258(97)00037-5. [DOI] [PubMed] [Google Scholar]
- 49.Proskuryakov S.Y., Konoplyannikov A.G., Gabai V.L. Necrosis: A Specific Form of Programmed Cell Death? Exp. Cell Res. 2003;283:1–16. doi: 10.1016/S0014-4827(02)00027-7. [DOI] [PubMed] [Google Scholar]
- 50.Vanden Berghe T., Linkermann A., Jouan-Lanhouet S., Walczak H., Vandenabeele P. Regulated Necrosis: The Expanding Network of Non-Apoptotic Cell Death Pathways. Nat. Rev. Mol. Cell Biol. 2014;15:135–147. doi: 10.1038/nrm3737. [DOI] [PubMed] [Google Scholar]
- 51.Vandenabeele P., Galluzzi L., Vanden Berghe T., Kroemer G. Molecular Mechanisms of Necroptosis: An Ordered Cellular Explosion. Nat. Rev. Mol. Cell Biol. 2010;11:700–714. doi: 10.1038/nrm2970. [DOI] [PubMed] [Google Scholar]
- 52.Jorgensen I., Miao E.A. Pyroptotic Cell Death Defends against Intracellular Pathogens. Immunol. Rev. 2015;265:130–142. doi: 10.1111/imr.12287. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53.Gong W., Shi Y., Ren J. Research Progresses of Molecular Mechanism of Pyroptosis and Its Related Diseases. Immunobiology. 2020;225:151884. doi: 10.1016/j.imbio.2019.11.019. [DOI] [PubMed] [Google Scholar]
- 54.David K.K., Andrabi S.A., Dawson T.M., Dawson V.L. Parthanatos, a Messenger of Death. Front. Biosci. Landmark Ed. 2009;14:1116–1128. doi: 10.2741/3297. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Vyas S., Chesarone-Cataldo M., Todorova T., Huang Y.-H., Chang P. A Systematic Analysis of the PARP Protein Family Identifies New Functions Critical for Cell Physiology. Nat. Commun. 2013;4:2240. doi: 10.1038/ncomms3240. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.Riegman M., Sagie L., Galed C., Levin T., Steinberg N., Dixon S.J., Wiesner U., Bradbury M.S., Niethammer P., Zaritsky A., et al. Ferroptosis Occurs through an Osmotic Mechanism and Propagates Independently of Cell Rupture. Nat. Cell Biol. 2020;22:1042–1048. doi: 10.1038/s41556-020-0565-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Yagoda N., von Rechenberg M., Zaganjor E., Bauer A.J., Yang W.S., Fridman D.J., Wolpaw A.J., Smukste I., Peltier J.M., Boniface J.J., et al. RAS–RAF–MEK-Dependent Oxidative Cell Death Involving Voltage-Dependent Anion Channels. Nature. 2007;447:865–869. doi: 10.1038/nature05859. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58.Friedmann Angeli J.P., Schneider M., Proneth B., Tyurina Y.Y., Tyurin V.A., Hammond V.J., Herbach N., Aichler M., Walch A., Eggenhofer E., et al. Inactivation of the Ferroptosis Regulator Gpx4 Triggers Acute Renal Failure in Mice. Nat. Cell Biol. 2014;16:1180–1191. doi: 10.1038/ncb3064. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.Wei S., Qiu T., Yao X., Wang N., Jiang L., Jia X., Tao Y., Wang Z., Pei P., Zhang J., et al. Arsenic Induces Pancreatic Dysfunction and Ferroptosis via Mitochondrial ROS-Autophagy-Lysosomal Pathway. J. Hazard. Mater. 2020;384:121390. doi: 10.1016/j.jhazmat.2019.121390. [DOI] [PubMed] [Google Scholar]
- 60.Li J., Cao F., Yin H., Huang Z., Lin Z., Mao N., Sun B., Wang G. Ferroptosis: Past, Present and Future. Cell Death Dis. 2020;11:88. doi: 10.1038/s41419-020-2298-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.An J.-R., Su J.-N., Sun G.-Y., Wang Q.-F., Fan Y.-D., Jiang N., Yang Y.-F., Shi Y. Liraglutide Alleviates Cognitive Deficit in Db/Db Mice: Involvement in Oxidative Stress, Iron Overload, and Ferroptosis. Neurochem. Res. 2021;47:279–294. doi: 10.1007/s11064-021-03442-7. [DOI] [PubMed] [Google Scholar]
- 62.Karmi O., Sohn Y.-S., Zandalinas S.I., Rowland L., King S., Nechushtai R., Mittler R. Disrupting CISD2 Function in Cancer Cells Primarily Impacts Mitochondrial Labile Iron Levels and Triggers TXNIP Expression. Free Radic. Biol. Med. 2021;176:92–104. doi: 10.1016/j.freeradbiomed.2021.09.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63.Alim I., Caulfield J.T., Chen Y., Swarup V., Geschwind D.H., Ivanova E., Seravalli J., Ai Y., Sansing L.H., Ste Marie E.J., et al. Selenium Drives a Transcriptional Adaptive Program to Block Ferroptosis and Treat Stroke. Cell. 2019;177:1262–1279. doi: 10.1016/j.cell.2019.03.032. [DOI] [PubMed] [Google Scholar]
- 64.Homma T., Kobayashi S., Fujii J. Cysteine Preservation Confers Resistance to Glutathione-Depleted Cells against Ferroptosis via CDGSH Iron Sulphur Domain-Containing Proteins (CISDs) Free Radic. Res. 2020;54:397–407. doi: 10.1080/10715762.2020.1780229. [DOI] [PubMed] [Google Scholar]
- 65.Jang S., Chapa-Dubocq X.R., Tyurina Y.Y., St Croix C.M., Kapralov A.A., Tyurin V.A., Bayır H., Kagan V.E., Javadov S. Elucidating the Contribution of Mitochondrial Glutathione to Ferroptosis in Cardiomyocytes. Redox Biol. 2021;45:102021. doi: 10.1016/j.redox.2021.102021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66.Dixon S.J., Patel D.N., Welsch M., Skouta R., Lee E.D., Hayano M., Thomas A.G., Gleason C.E., Tatonetti N.P., Slusher B.S., et al. Pharmacological Inhibition of Cystine-Glutamate Exchange Induces Endoplasmic Reticulum Stress and Ferroptosis. eLife. 2014;3:e02523. doi: 10.7554/eLife.02523. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67.Chen X., Kang R., Kroemer G., Tang D. Organelle-Specific Regulation of Ferroptosis. Cell Death Differ. 2021;28:2843–2856. doi: 10.1038/s41418-021-00859-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68.Guo J., Duan L., He X., Li S., Wu Y., Xiang G., Bao F., Yang L., Shi H., Gao M., et al. A Combined Model of Human IPSC-Derived Liver Organoids and Hepatocytes Reveals Ferroptosis in DGUOK Mutant MtDNA Depletion Syndrome. Adv. Sci. 2021;8:2004680. doi: 10.1002/advs.202004680. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69.Stockwell B.R., Angeli J.P.F., Bayir H., Bush A.I., Conrad M., Dixon S., Fulda S., Gascon S., Hatzios S.K., Kagan V., et al. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell. 2017;171:273–285. doi: 10.1016/j.cell.2017.09.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70.Yang H., Rivera Z., Jube S., Nasu M., Bertino P., Goparaju C., Franzoso G., Lotze M.T., Krausz T., Pass H.I., et al. Programmed Necrosis Induced by Asbestos in Human Mesothelial Cells Causes High-Mobility Group Box 1 Protein Release and Resultant Inflammation. Proc. Natl. Acad. Sci. USA. 2010;107:12611–12616. doi: 10.1073/pnas.1006542107. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 71.Mou Y., Wang J., Wu J., He D., Zhang C., Duan C., Li B. Ferroptosis, a New Form of Cell Death: Opportunities and Challenges in Cancer. J. Hematol. Oncol. 2019;12:34. doi: 10.1186/s13045-019-0720-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 72.Shimada K., Skouta R., Kaplan A., Yang W.S., Hayano M., Dixon S.J., Brown L.M., Valenzuela C.A., Wolpaw A.J., Stockwell B.R. Global Survey of Cell Death Mechanisms Reveals Metabolic Regulation of Ferroptosis. Nat. Chem. Biol. 2016;12:497–503. doi: 10.1038/nchembio.2079. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 73.Hou W., Xie Y., Song X., Sun X., Lotze M.T., Zeh H.J., Kang R., Tang D. Autophagy Promotes Ferroptosis by Degradation of Ferritin. Autophagy. 2016;12:1425–1428. doi: 10.1080/15548627.2016.1187366. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 74.Feng H., Schorpp K., Jin J., Yozwiak C.E., Hoffstrom B.G., Decker A.M., Rajbhandari P., Stokes M.E., Bender H.G., Csuka J.M., et al. Transferrin Receptor Is a Specific Ferroptosis Marker. Cell Rep. 2020;30:3411–3423. doi: 10.1016/j.celrep.2020.02.049. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 75.Doll S., Proneth B., Tyurina Y.Y., Panzilius E., Kobayashi S., Ingold I., Irmler M., Beckers J., Aichler M., Walch A., et al. Acsl4 Dictates Ferroptosis Sensitivity by Shaping Cellular Lipid Composition. Nat. Chem. Biol. 2017;13:91–98. doi: 10.1038/nchembio.2239. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 76.Dixon S.J., Winter G.E., Musavi L.S., Lee E.D., Snijder B., Rebsamen M., Superti-Furga G., Stockwell B.R. Human Haploid Cell Genetics Reveals Roles for Lipid Metabolism Genes in Nonapoptotic Cell Death. ACS Chem. Biol. 2015;10:1604–1609. doi: 10.1021/acschembio.5b00245. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 77.Yang W.S., Kim K.J., Gaschler M.M., Patel M., Shchepinov M.S., Stockwell B.R. Peroxidation of Polyunsaturated Fatty Acids by Lipoxygenases Drives Ferroptosis. Proc. Natl. Acad. Sci. USA. 2016;113:E4966–E4975. doi: 10.1073/pnas.1603244113. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 78.Park T.-J., Park J.H., Lee G.S., Lee J.-Y., Shin J.H., Kim M.W., Kim Y.S., Kim J.-Y., Oh K.-J., Han B.-S., et al. Quantitative Proteomic Analyses Reveal That GPX4 Downregulation during Myocardial Infarction Contributes to Ferroptosis in Cardiomyocytes. Cell Death Dis. 2019;10:835. doi: 10.1038/s41419-019-2061-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 79.Doll S., Conrad M. Iron and Ferroptosis: A Still Ill-defined Liaison. IUBMB Life. 2017;69:423–434. doi: 10.1002/iub.1616. [DOI] [PubMed] [Google Scholar]
- 80.Fradejas N., Carlson B.A., Rijntjes E., Becker N.-P., Tobe R., Schweizer U. Mammalian Trit1 Is a TRNA([Ser]Sec)-Isopentenyl Transferase Required for Full Selenoprotein Expression. Biochem. J. 2013;450:427–432. doi: 10.1042/BJ20121713. [DOI] [PubMed] [Google Scholar]
- 81.Cardoso B.R., Hare D.J., Bush A.I., Roberts B.R. Glutathione Peroxidase 4: A New Player in Neurodegeneration? Mol. Psychiatry. 2017;22:328–335. doi: 10.1038/mp.2016.196. [DOI] [PubMed] [Google Scholar]
- 82.Gaucher C., Boudier A., Bonetti J., Clarot I., Leroy P., Parent M. Glutathione: Antioxidant Properties Dedicated to Nanotechnologies. Antioxidants. 2018;7:62. doi: 10.3390/antiox7050062. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 83.Hassannia B., Vandenabeele P., Berghe T.V. Targeting Ferroptosis to Iron Out Cancer. Cancer Cell. 2019;35:830–849. doi: 10.1016/j.ccell.2019.04.002. [DOI] [PubMed] [Google Scholar]
- 84.Cao J.Y., Dixon S.J. Mechanisms of Ferroptosis. Cell. Mol. Life Sci. 2016;73:2195–2209. doi: 10.1007/s00018-016-2194-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 85.Gao M., Monian P., Quadri N., Ramasamy R., Jiang X. Glutaminolysis and Transferrin Regulate Ferroptosis. Mol. Cell. 2015;59:298–308. doi: 10.1016/j.molcel.2015.06.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 86.Guo J., Xu B., Han Q., Zhou H., Xia Y., Gong C., Dai X., Li Z., Wu G. Ferroptosis: A Novel Anti-Tumor Action for Cisplatin. Cancer Res. Treat. Off. J. Korean Cancer Assoc. 2018;50:445–460. doi: 10.4143/crt.2016.572. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 87.Chen L., Li X., Liu L., Yu B., Xue Y., Liu Y. Erastin Sensitizes Glioblastoma Cells to Temozolomide by Restraining XCT and Cystathionine-γ-Lyase Function. Oncol. Rep. 2015;33:1465–1474. doi: 10.3892/or.2015.3712. [DOI] [PubMed] [Google Scholar]
- 88.Yamaguchi H., Hsu J.L., Chen C.-T., Wang Y.-N., Hsu M.-C., Chang S.-S., Du Y., Ko H.-W., Herbst R., Hung M.-C. Caspase-Independent Cell Death Is Involved in the Negative Effect of EGFR Inhibitors on Cisplatin in Non-Small Cell Lung Cancer Cells. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2013;19:845–854. doi: 10.1158/1078-0432.CCR-12-2621. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 89.Sato M., Kusumi R., Hamashima S., Kobayashi S., Sasaki S., Komiyama Y., Izumikawa T., Conrad M., Bannai S., Sato H. The Ferroptosis Inducer Erastin Irreversibly Inhibits System xc− and Synergizes with Cisplatin to Increase Cisplatin’s Cytotoxicity in Cancer Cells. Sci. Rep. 2018;8:968. doi: 10.1038/s41598-018-19213-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 90.Roh J.-L., Kim E.H., Jang H.J., Park J.Y., Shin D. Induction of Ferroptotic Cell Death for Overcoming Cisplatin Resistance of Head and Neck Cancer. Cancer Lett. 2016;381:96–103. doi: 10.1016/j.canlet.2016.07.035. [DOI] [PubMed] [Google Scholar]
- 91.Pan X., Lin Z., Jiang D., Yu Y., Yang D., Zhou H., Zhan D., Liu S., Peng G., Chen Z., et al. Erastin Decreases Radioresistance of NSCLC Cells Partially by Inducing GPX4-mediated Ferroptosis. Oncol. Lett. 2019;17:3001–3008. doi: 10.3892/ol.2019.9888. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 92.Shibata Y., Yasui H., Higashikawa K., Miyamoto N., Kuge Y. Erastin, a Ferroptosis-Inducing Agent, Sensitized Cancer Cells to X-Ray Irradiation via Glutathione Starvation In Vitro and In Vivo. PLoS ONE. 2019;14:e0225931. doi: 10.1371/journal.pone.0225931. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 93.Cobler L., Zhang H., Suri P., Park C., Timmerman L.A. XCT Inhibition Sensitizes Tumors to γ-Radiation via Glutathione Reduction. Oncotarget. 2018;9:32280–32297. doi: 10.18632/oncotarget.25794. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 94.Zhang Y., Tan H., Daniels J.D., Zandkarimi F., Liu H., Brown L.M., Uchida K., O’Connor O.A., Stockwell B.R. Imidazole Ketone Erastin Induces Ferroptosis and Slows Tumor Growth in a Mouse Lymphoma Model. Cell Chem. Biol. 2019;26:623–633. doi: 10.1016/j.chembiol.2019.01.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 95.Yang W.S., SriRamaratnam R., Welsch M.E., Shimada K., Skouta R., Viswanathan V.S., Cheah J.H., Clemons P.A., Shamji A.F., Clish C.B., et al. Regulation of Ferroptotic Cancer Cell Death by GPX4. Cell. 2014;156:317–331. doi: 10.1016/j.cell.2013.12.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 96.Takayama T., Kubo T., Morikawa A., Morita T., Nagano O., Saya H. Potential of Sulfasalazine as a Therapeutic Sensitizer for CD44 Splice Variant 9-Positive Urogenital Cancer. Med. Oncol. 2016;33:45. doi: 10.1007/s12032-016-0760-x. [DOI] [PubMed] [Google Scholar]
- 97.Ma M.-Z., Chen G., Wang P., Lu W.-H., Zhu C.-F., Song M., Yang J., Wen S., Xu R.-H., Hu Y., et al. Xc− Inhibitor Sulfasalazine Sensitizes Colorectal Cancer to Cisplatin by a GSH-Dependent Mechanism. Cancer Lett. 2015;368:88–96. doi: 10.1016/j.canlet.2015.07.031. [DOI] [PubMed] [Google Scholar]
- 98.Lachaier E., Louandre C., Godin C., Saidak Z., Baert M., Diouf M., Chauffert B., Galmiche A. Sorafenib Induces Ferroptosis in Human Cancer Cell Lines Originating from Different Solid Tumors. Anticancer Res. 2014;34:6417–6422. [PubMed] [Google Scholar]
- 99.Louandre C., Ezzoukhry Z., Godin C., Barbare J.-C., Mazière J.-C., Chauffert B., Galmiche A. Iron-Dependent Cell Death of Hepatocellular Carcinoma Cells Exposed to Sorafenib. Int. J. Cancer. 2013;133:1732–1742. doi: 10.1002/ijc.28159. [DOI] [PubMed] [Google Scholar]
- 100.Guo W., Zhao Y., Zhang Z., Tan N., Zhao F., Ge C., Liang L., Jia D., Chen T., Yao M., et al. Disruption of XCT Inhibits Cell Growth via the ROS/Autophagy Pathway in Hepatocellular Carcinoma. Cancer Lett. 2011;312:55–61. doi: 10.1016/j.canlet.2011.07.024. [DOI] [PubMed] [Google Scholar]
- 101.Gout P.W., Buckley A.R., Simms C.R., Bruchovsky N. Sulfasalazine, a Potent Suppressor of Lymphoma Growth by Inhibition of the xc− Cystine Transporter: A New Action for an Old Drug. Leukemia. 2001;15:1633–1640. doi: 10.1038/sj.leu.2402238. [DOI] [PubMed] [Google Scholar]
- 102.Cramer S.L., Saha A., Liu J., Tadi S., Tiziani S., Yan W., Triplett K., Lamb C., Alters S.E., Rowlinson S., et al. Systemic Depletion of L-Cyst(e)Ine with Cyst(e)Inase Increases Reactive Oxygen Species and Suppresses Tumor Growth. Nat. Med. 2017;23:120–127. doi: 10.1038/nm.4232. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 103.Shin D., Kim E.H., Lee J., Roh J.-L. Nrf2 Inhibition Reverses Resistance to GPX4 Inhibitor-Induced Ferroptosis in Head and Neck Cancer. Free Radic. Biol. Med. 2018;129:454–462. doi: 10.1016/j.freeradbiomed.2018.10.426. [DOI] [PubMed] [Google Scholar]
- 104.Sui X., Zhang R., Liu S., Duan T., Zhai L., Zhang M., Han X., Xiang Y., Huang X., Lin H., et al. RSL3 Drives Ferroptosis Through GPX4 Inactivation and ROS Production in Colorectal Cancer. Front. Pharmacol. 2018;9:1371. doi: 10.3389/fphar.2018.01371. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 105.Hassannia B., Wiernicki B., Ingold I., Qu F., Van Herck S., Tyurina Y.Y., Bayır H., Abhari B.A., Angeli J.P.F., Choi S.M., et al. Nano-Targeted Induction of Dual Ferroptotic Mechanisms Eradicates High-Risk Neuroblastoma. J. Clin. Investig. 2018;128:3341–3355. doi: 10.1172/JCI99032. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 106.Woo J.H., Shimoni Y., Yang W.S., Subramaniam P., Iyer A., Nicoletti P., Rodríguez Martínez M., López G., Mattioli M., Realubit R., et al. Elucidating Compound Mechanism of Action by Network Perturbation Analysis. Cell. 2015;162:441–451. doi: 10.1016/j.cell.2015.05.056. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 107.Eaton J.K., Furst L., Ruberto R.A., Moosmayer D., Hillig R.C., Hilpmann A., Zimmermann K., Ryan M.J., Niehues M., Badock V., et al. Targeting a Therapy-Resistant Cancer Cell State Using Masked Electrophiles as GPX4 Inhibitors. Cold Spring Harbor Laboratory; New York, NY, USA: 2018. p. 376764. [Google Scholar]
- 108.Weïwer M., Bittker J.A., Lewis T.A., Shimada K., Yang W.S., MacPherson L., Dandapani S., Palmer M., Stockwell B.R., Schreiber S.L., et al. Development of Small-Molecule Probes That Selectively Kill Cells Induced to Express Mutant RAS. Bioorg. Med. Chem. Lett. 2012;22:1822–1826. doi: 10.1016/j.bmcl.2011.09.047. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 109.Sun Y., Berleth N., Wu W., Schlütermann D., Deitersen J., Stuhldreier F., Berning L., Friedrich A., Akgün S., Mendiburo M.J., et al. Fin56-Induced Ferroptosis Is Supported by Autophagy-Mediated GPX4 Degradation and Functions Synergistically with MTOR Inhibition to Kill Bladder Cancer Cells. Cell Death Dis. 2021;12:1028. doi: 10.1038/s41419-021-04306-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 110.Gaschler M.M., Andia A.A., Liu H., Csuka J.M., Hurlocker B., Vaiana C.A., Heindel D.W., Zuckerman D.S., Bos P.H., Reznik E., et al. FINO2 Initiates Ferroptosis through GPX4 Inactivation and Iron Oxidation. Nat. Chem. Biol. 2018;14:507–515. doi: 10.1038/s41589-018-0031-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 111.Chang L.-C., Chiang S.-K., Chen S.-E., Yu Y.-L., Chou R.-H., Chang W.-C. Heme Oxygenase-1 Mediates BAY 11-7085 Induced Ferroptosis. Cancer Lett. 2018;416:124–137. doi: 10.1016/j.canlet.2017.12.025. [DOI] [PubMed] [Google Scholar]
- 112.Ma S., Henson E.S., Chen Y., Gibson S.B. Ferroptosis Is Induced Following Siramesine and Lapatinib Treatment of Breast Cancer Cells. Cell Death Dis. 2016;7:e2307. doi: 10.1038/cddis.2016.208. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 113.Yao X., Zhang Y., Hao J., Duan H.-Q., Zhao C.-X., Sun C., Li B., Fan B.-Y., Wang X., Li W.-X., et al. Deferoxamine Promotes Recovery of Traumatic Spinal Cord Injury by Inhibiting Ferroptosis. Neural Regen. Res. 2019;14:532–541. doi: 10.4103/1673-5374.245480. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 114.Do Van B., Gouel F., Jonneaux A., Timmerman K., Gelé P., Pétrault M., Bastide M., Laloux C., Moreau C., Bordet R., et al. Ferroptosis, a Newly Characterized Form of Cell Death in Parkinson’s Disease That Is Regulated by PKC. Neurobiol. Dis. 2016;94:169–178. doi: 10.1016/j.nbd.2016.05.011. [DOI] [PubMed] [Google Scholar]
- 115.Otsu W., Ishida K., Chinen N., Nakamura S., Shimazawa M., Tsusaki H., Hara H. Cigarette Smoke Extract and Heated Tobacco Products Promote Ferritin Cleavage and Iron Accumulation in Human Corneal Epithelial Cells. Sci. Rep. 2021;11:18555. doi: 10.1038/s41598-021-97956-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 116.Chen M.-S., Wang S.-F., Hsu C.-Y., Yin P.-H., Yeh T.-S., Lee H.-C., Tseng L.-M. CHAC1 Degradation of Glutathione Enhances Cystine-Starvation-Induced Necroptosis and Ferroptosis in Human Triple Negative Breast Cancer Cells via the GCN2-EIF2α-ATF4 Pathway. Oncotarget. 2017;8:114588–114602. doi: 10.18632/oncotarget.23055. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 117.Barnabé N., Zastre J.A., Venkataram S., Hasinoff B.B. Deferiprone Protects against Doxorubicin-Induced Myocyte Cytotoxicity. Free Radic. Biol. Med. 2002;33:266–275. doi: 10.1016/S0891-5849(02)00873-0. [DOI] [PubMed] [Google Scholar]
- 118.Miotto G., Rossetto M., Di Paolo M.L., Orian L., Venerando R., Roveri A., Vučković A.-M., Bosello Travain V., Zaccarin M., Zennaro L., et al. Insight into the Mechanism of Ferroptosis Inhibition by Ferrostatin-1. Redox Biol. 2020;28:101328. doi: 10.1016/j.redox.2019.101328. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 119.Wu C., Zhao W., Yu J., Li S., Lin L., Chen X. Induction of Ferroptosis and Mitochondrial Dysfunction by Oxidative Stress in PC12 Cells. Sci. Rep. 2018;8:574. doi: 10.1038/s41598-017-18935-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 120.Li D., Zhang M., Chao H. Significance of Glutathione Peroxidase 4 and Intracellular Iron Level in Ovarian Cancer Cells-”utilization” of Ferroptosis Mechanism. Inflamm. Res. Off. J. Eur. Histamine Res. Soc. Al. 2021;70:1177–1189. doi: 10.1007/s00011-021-01495-6. [DOI] [PubMed] [Google Scholar]
- 121.Hinman A., Holst C.R., Latham J.C., Bruegger J.J., Ulas G., McCusker K.P., Amagata A., Davis D., Hoff K.G., Kahn-Kirby A.H., et al. Vitamin E Hydroquinone Is an Endogenous Regulator of Ferroptosis via Redox Control of 15-Lipoxygenase. PLoS ONE. 2018;13:e0201369. doi: 10.1371/journal.pone.0201369. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 122.Princen H.M.G., van Duyvenvoorde W., Buytenhek R., van der Laarse A., van Poppel G., Leuven J.A.G., van Hinsbergh V.W.M. Supplementation With Low Doses of Vitamin E Protects LDL From Lipid Peroxidation in Men and Women. Arterioscler. Thromb. Vasc. Biol. 1995;15:325–333. doi: 10.1161/01.ATV.15.3.325. [DOI] [PubMed] [Google Scholar]
- 123.Yamada N., Karasawa T., Kimura H., Watanabe S., Komada T., Kamata R., Sampilvanjil A., Ito J., Nakagawa K., Kuwata H., et al. Ferroptosis Driven by Radical Oxidation of N-6 Polyunsaturated Fatty Acids Mediates Acetaminophen-Induced Acute Liver Failure. Cell Death Dis. 2020;11:144. doi: 10.1038/s41419-020-2334-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 124.Li C., Chen J.W., Liu Z.H., Shen Y., Ding F.H., Gu G., Liu J., Qiu J.P., Gao J., Zhang R.Y., et al. CTRP5 Promotes Transcytosis and Oxidative Modification of Low-Density Lipoprotein and the Development of Atherosclerosis. Atherosclerosis. 2018;278:197–209. doi: 10.1016/j.atherosclerosis.2018.09.037. [DOI] [PubMed] [Google Scholar]
- 125.Hörkkö S., Bird D.A., Miller E., Itabe H., Leitinger N., Subbanagounder G., Berliner J.A., Friedman P., Dennis E.A., Curtiss L.K., et al. Monoclonal Autoantibodies Specific for Oxidized Phospholipids or Oxidized Phospholipid–Protein Adducts Inhibit Macrophage Uptake of Oxidized Low-Density Lipoproteins. J. Clin. Investig. 1999;103:117–128. doi: 10.1172/JCI4533. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 126.Marques V.B., Leal M.A.S., Mageski J.G.A., Fidelis H.G., Nogueira B.V., Vasquez E.C., Meyrelles S.D.S., Simões M.R., Dos Santos L. Chronic Iron Overload Intensifies Atherosclerosis in Apolipoprotein E Deficient Mice: Role of Oxidative Stress and Endothelial Dysfunction. Life Sci. 2019;233:116702. doi: 10.1016/j.lfs.2019.116702. [DOI] [PubMed] [Google Scholar]
- 127.Li W., Xu L.-H., Forssell C., Sullivan J.L., Yuan X.-M. Overexpression of Transferrin Receptor and Ferritin Related to Clinical Symptoms and Destabilization of Human Carotid Plaques. Exp. Biol. Med. 2008;233:818–826. doi: 10.3181/0711-RM-320. [DOI] [PubMed] [Google Scholar]
- 128.Vinchi F., Porto G., Simmelbauer A., Altamura S., Passos S.T., Garbowski M., Silva A.M.N., Spaich S., Seide S.E., Sparla R., et al. Atherosclerosis Is Aggravated by Iron Overload and Ameliorated by Dietary and Pharmacological Iron Restriction. Eur. Heart J. 2020;41:2681–2695. doi: 10.1093/eurheartj/ehz112. [DOI] [PubMed] [Google Scholar]
- 129.Kapralov A.A., Yang Q., Dar H.H., Tyurina Y.Y., Anthonymuthu T.S., Kim R., St Croix C.M., Mikulska-Ruminska K., Liu B., Shrivastava I.H., et al. Redox Lipid Reprogramming Commands Susceptibility of Macrophages and Microglia to Ferroptotic Death. Nat. Chem. Biol. 2020;16:278–290. doi: 10.1038/s41589-019-0462-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 130.Sindrilaru A., Peters T., Wieschalka S., Baican C., Baican A., Peter H., Hainzl A., Schatz S., Qi Y., Schlecht A., et al. An Unrestrained Proinflammatory M1 Macrophage Population Induced by Iron Impairs Wound Healing in Humans and Mice. J. Clin. Investig. 2011;121:985–997. doi: 10.1172/JCI44490. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 131.Marques L., Negre-Salvayre A., Costa L., Canonne-Hergaux F. Iron Gene Expression Profile in Atherogenic Mox Macrophages. Biochim. Biophys. Acta. 2016;1862:1137–1146. doi: 10.1016/j.bbadis.2016.03.004. [DOI] [PubMed] [Google Scholar]
- 132.Marcil V., Lavoie J.C., Emonnot L., Seidman E., Levy E. Analysis of the Effects of Iron and Vitamin C Co-Supplementation on Oxidative Damage, Antioxidant Response and Inflammation in THP-1 Macrophages. Clin. Biochem. 2011;44:873–883. doi: 10.1016/j.clinbiochem.2011.04.012. [DOI] [PubMed] [Google Scholar]
- 133.Sampilvanjil A., Karasawa T., Yamada N., Komada T., Higashi T., Baatarjav C., Watanabe S., Kamata R., Ohno N., Takahashi M. Cigarette Smoke Extract Induces Ferroptosis in Vascular Smooth Muscle Cells. Am. J. Physiol. Heart Circ. Physiol. 2020;318:H508–H518. doi: 10.1152/ajpheart.00559.2019. [DOI] [PubMed] [Google Scholar]
- 134.Howard G., Wagenknecht L.E., Burke G.L., Diez-Roux A., Evans G.W., McGovern P., Nieto F.J., Tell G.S. Cigarette Smoking and Progression of Atherosclerosis: The Atherosclerosis Risk in Communities (ARIC) Study. JAMA. 1998;279:119–124. doi: 10.1001/jama.279.2.119. [DOI] [PubMed] [Google Scholar]
- 135.Guo Z., Ran Q., Roberts L.J., Zhou L., Richardson A., Sharan C., Wu D., Yang H. Suppression of Atherogenesis by Overexpression of Glutathione Peroxidase-4 in Apolipoprotein E-Deficient Mice. Free Radic. Biol. Med. 2008;44:343–352. doi: 10.1016/j.freeradbiomed.2007.09.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 136.Wójcicki J., Rózewicka L., Barcew-Wiszniewska B., Samochowiec L., Juźwiak S., Kadłubowska D., Tustanowski S., Juzyszyn Z. Effect of Selenium and Vitamin E on the Development of Experimental Atherosclerosis in Rabbits. Atherosclerosis. 1991;87:9–16. doi: 10.1016/0021-9150(91)90227-T. [DOI] [PubMed] [Google Scholar]
- 137.Schwenke D.C., Behr S.R. Vitamin E Combined with Selenium Inhibits Atherosclerosis in Hypercholesterolemic Rabbits Independently of Effects on Plasma Cholesterol Concentrations. Circ. Res. 1998;83:366–377. doi: 10.1161/01.RES.83.4.366. [DOI] [PubMed] [Google Scholar]
- 138.Mehta U., Kang B.P.S., Kukreja R.S., Bansal M.P. Ultrastructural Examination of Rabbit Aortic Wall Following High-Fat Diet Feeding and Selenium Supplementation: A Transmission Electron Microscopy Study. J. Appl. Toxicol. JAT. 2002;22:405–413. doi: 10.1002/jat.877. [DOI] [PubMed] [Google Scholar]
- 139.Liu H., Xu H., Huang K. Selenium in the Prevention of Atherosclerosis and Its Underlying Mechanisms. Met. Integr. Biometal Sci. 2017;9:21–37. doi: 10.1039/C6MT00195E. [DOI] [PubMed] [Google Scholar]
- 140.Veiner H.-L., Gorbatov R., Vardi M., Doros G., Miller-Lotan R., Zohar Y., Sabo E., Asleh R., Levy N.S., Goldfarb L.J., et al. Pharmacogenomic Interaction between the Haptoglobin Genotype and Vitamin E on Atherosclerotic Plaque Progression and Stability. Atherosclerosis. 2015;239:232–239. doi: 10.1016/j.atherosclerosis.2015.01.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 141.Zhang W.-J., Wei H., Frei B. The Iron Chelator, Desferrioxamine, Reduces Inflammation and Atherosclerotic Lesion Development in Experimental Mice. Exp. Biol. Med. 2010;235:633–641. doi: 10.1258/ebm.2009.009229. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 142.Wang Y., Tang M. PM2.5 Induces Ferroptosis in Human Endothelial Cells through Iron Overload and Redox Imbalance. Environ. Pollut. 2019;254:112937. doi: 10.1016/j.envpol.2019.07.105. [DOI] [PubMed] [Google Scholar]
- 143.Gujja P., Rosing D.R., Tripodi D.J., Shizukuda Y. Iron Overload Cardiomyopathy. J. Am. Coll. Cardiol. 2010;56:1001–1012. doi: 10.1016/j.jacc.2010.03.083. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 144.Ravingerová T., Kindernay L., Barteková M., Ferko M., Adameová A., Zohdi V., Bernátová I., Ferenczyová K., Lazou A. The Molecular Mechanisms of Iron Metabolism and Its Role in Cardiac Dysfunction and Cardioprotection. Int. J. Mol. Sci. 2020;21:7889. doi: 10.3390/ijms21217889. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 145.Koleini N., Nickel B.E., Edel A.L., Fandrich R.R., Ravandi A., Kardami E. Oxidized Phospholipids in Doxorubicin-Induced Cardiotoxicity. Chem. Biol. Interact. 2019;303:35–39. doi: 10.1016/j.cbi.2019.01.032. [DOI] [PubMed] [Google Scholar]
- 146.Li W., Feng G., Gauthier J.M., Lokshina I., Higashikubo R., Evans S., Liu X., Hassan A., Tanaka S., Cicka M., et al. Ferroptotic Cell Death and TLR4/Trif Signaling Initiate Neutrophil Recruitment after Heart Transplantation. J. Clin. Investig. 2019;129:2293–2304. doi: 10.1172/JCI126428. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 147.Fang X., Wang H., Han D., Xie E., Yang X., Wei J., Gu S., Gao F., Zhu N., Yin X., et al. Ferroptosis as a Target for Protection against Cardiomyopathy. Proc. Natl. Acad. Sci. USA. 2019;116:2672–2680. doi: 10.1073/pnas.1821022116. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 148.Feng Y., Madungwe N.B., Imam Aliagan A.D., Tombo N., Bopassa J.C. Liproxstatin-1 Protects the Mouse Myocardium against Ischemia/Reperfusion Injury by Decreasing VDAC1 Levels and Restoring GPX4 Levels. Biochem. Biophys. Res. Commun. 2019;520:606–611. doi: 10.1016/j.bbrc.2019.10.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 149.Sun C., Peng F., Li J., Cui X., Qiao X., Zhu W. Ferroptosis-Specific Inhibitor Ferrostatin-1 Relieves H2O2-Induced Redox Imbalance in Primary Cardiomyocytes through the Nrf2/ARE Pathway. Dis. Markers. 2022;2022:4539932. doi: 10.1155/2022/4539932. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 150.Li N., Jiang W., Wang W., Xiong R., Wu X., Geng Q. Ferroptosis and Its Emerging Roles in Cardiovascular Diseases. Pharmacol. Res. 2021;166:105466. doi: 10.1016/j.phrs.2021.105466. [DOI] [PubMed] [Google Scholar]
- 151.Johnson W.M., Wilson-Delfosse A.L., Mieyal J.J. Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases. Nutrients. 2012;4:1399–1440. doi: 10.3390/nu4101399. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 152.Ross C.A., Tabrizi S.J. Huntington’s Disease: From Molecular Pathogenesis to Clinical Treatment. Lancet Neurol. 2011;10:83–98. doi: 10.1016/S1474-4422(10)70245-3. [DOI] [PubMed] [Google Scholar]
- 153.Sadagurski M., Cheng Z., Rozzo A., Palazzolo I., Kelley G.R., Dong X., Krainc D., White M.F. IRS2 Increases Mitochondrial Dysfunction and Oxidative Stress in a Mouse Model of Huntington Disease. J. Clin. Investig. 2011;121:4070–4081. doi: 10.1172/JCI46305. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 154.Chen J., Marks E., Lai B., Zhang Z., Duce J.A., Lam L.Q., Volitakis I., Bush A.I., Hersch S., Fox J.H. Iron Accumulates in Huntington’s Disease Neurons: Protection by Deferoxamine. PLoS ONE. 2013;8:e77023. doi: 10.1371/journal.pone.0077023. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 155.Youdim M.B., Riederer P. The Role of Iron in Senescence of Dopaminergic Neurons in Parkinson’s Disease. J. Neural Transm. Suppl. 1993;40:57–67. [PubMed] [Google Scholar]
- 156.Morris C.M., Edwardson J.A. Iron Histochemistry of the Substantia Nigra in Parkinson’s Disease. Neurodegener. J. Neurodegener. Disord. Neuroprot. Neuroregener. 1994;3:277–282. [PubMed] [Google Scholar]
- 157.Mann V.M., Cooper J.M., Daniel S.E., Srai K., Jenner P., Marsden C.D., Schapira A.H. Complex I, Iron, and Ferritin in Parkinson’s Disease Substantia Nigra. Ann. Neurol. 1994;36:876–881. doi: 10.1002/ana.410360612. [DOI] [PubMed] [Google Scholar]
- 158.Molina J.A., Jiménez-Jiménez F.J., Fernandez-Calle P., Lalinde L., Tenias J.M., Pondal M., Vazquez A., Codoceo R. Serum Lipid Peroxides in Patients with Parkinson’s Disease. Neurosci. Lett. 1992;136:137–140. doi: 10.1016/0304-3940(92)90033-4. [DOI] [PubMed] [Google Scholar]
- 159.Dexter D.T., Carter C.J., Wells F.R., Javoy-Agid F., Agid Y., Lees A., Jenner P., Marsden C.D. Basal Lipid Peroxidation in Substantia Nigra Is Increased in Parkinson’s Disease. J. Neurochem. 1989;52:381–389. doi: 10.1111/j.1471-4159.1989.tb09133.x. [DOI] [PubMed] [Google Scholar]
- 160.Przedborski S., Ischiropoulos H. Reactive Oxygen and Nitrogen Species: Weapons of Neuronal Destruction in Models of Parkinson’s Disease. Antioxid. Redox Signal. 2005;7:685–693. doi: 10.1089/ars.2005.7.685. [DOI] [PubMed] [Google Scholar]
- 161.Tieu K., Ischiropoulos H., Przedborski S. Nitric Oxide and Reactive Oxygen Species in Parkinson’s Disease. IUBMB Life. 2003;55:329–335. doi: 10.1080/1521654032000114320. [DOI] [PubMed] [Google Scholar]
- 162.Hirsch E.C. Does Oxidative Stress Participate in Nerve Cell Death in Parkinson’s Disease? Eur. Neurol. 1993;33((Suppl. S1)):52–59. doi: 10.1159/000118538. [DOI] [PubMed] [Google Scholar]
- 163.Magaki S., Raghavan R., Mueller C., Oberg K.C., Vinters H.V., Kirsch W.M. Iron, Copper, and Iron Regulatory Protein 2 in Alzheimer’s Disease and Related Dementias. Neurosci. Lett. 2007;418:72–76. doi: 10.1016/j.neulet.2007.02.077. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 164.Morris C.M., Kerwin J.M., Edwardson J.A. Non-Haem Iron Histochemistry of the Normal and Alzheimer’s Disease Hippocampus. Neurodegener. J. Neurodegener. Disord. Neuroprot. Neuroregener. 1994;3:267–275. [PubMed] [Google Scholar]
- 165.Piñero D.J., Hu J., Connor J.R. Alterations in the Interaction between Iron Regulatory Proteins and Their Iron Responsive Element in Normal and Alzheimer’s Diseased Brains. Cell. Mol. Biol. 2000;46:761–776. [PubMed] [Google Scholar]
- 166.Lovell M.A., Markesbery W.R. Oxidative DNA Damage in Mild Cognitive Impairment and Late-Stage Alzheimer’s Disease. Nucleic Acids Res. 2007;35:7497–7504. doi: 10.1093/nar/gkm821. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 167.Dei R., Takeda A., Niwa H., Li M., Nakagomi Y., Watanabe M., Inagaki T., Washimi Y., Yasuda Y., Horie K., et al. Lipid Peroxidation and Advanced Glycation End Products in the Brain in Normal Aging and in Alzheimer’s Disease. Acta Neuropathol. 2002;104:113–122. doi: 10.1007/s00401-002-0523-y. [DOI] [PubMed] [Google Scholar]
- 168.Singh M., Dang T.N., Arseneault M., Ramassamy C. Role of By-Products of Lipid Oxidation in Alzheimer’s Disease Brain: A Focus on Acrolein. J. Alzheimer’s Dis. JAD. 2010;21:741–756. doi: 10.3233/JAD-2010-100405. [DOI] [PubMed] [Google Scholar]
- 169.Xu Y., Zhao J., Zhao Y., Zhou L., Qiao H., Xu Q., Liu Y. The Role of Ferroptosis in Neurodegenerative Diseases. Mol. Biol. Rep. 2022;52:1655–1661. doi: 10.1007/s11033-022-08048-y. [DOI] [PubMed] [Google Scholar]
- 170.Weiland A., Wang Y., Wu W., Lan X., Han X., Li Q., Wang J. Ferroptosis and Its Role in Diverse Brain Diseases. Mol. Neurobiol. 2019;56:4880–4893. doi: 10.1007/s12035-018-1403-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 171.Reichert C.O., de Freitas F.A., Sampaio-Silva J., Rokita-Rosa L., de Lima Barros P., Levy D., Bydlowski S.P. Ferroptosis Mechanisms Involved in Neurodegenerative Diseases. Int. J. Mol. Sci. 2020;21:8765. doi: 10.3390/ijms21228765. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 172.Hambright W.S., Fonseca R.S., Chen L., Na R., Ran Q. Ablation of Ferroptosis Regulator Glutathione Peroxidase 4 in Forebrain Neurons Promotes Cognitive Impairment and Neurodegeneration. Redox Biol. 2017;12:8–17. doi: 10.1016/j.redox.2017.01.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 173.Ingold I., Berndt C., Schmitt S., Doll S., Poschmann G., Buday K., Roveri A., Peng X., Porto Freitas F., Seibt T., et al. Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis. Cell. 2018;172:409–422. doi: 10.1016/j.cell.2017.11.048. [DOI] [PubMed] [Google Scholar]
- 174.Aoyama K. Glutathione in the Brain. Int. J. Mol. Sci. 2021;22:5010. doi: 10.3390/ijms22095010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 175.Robert S.M., Ogunrinu-Babarinde T., Holt K.T., Sontheimer H. Role of Glutamate Transporters in Redox Homeostasis of the Brain. Neurochem. Int. 2014;73:181–191. doi: 10.1016/j.neuint.2014.01.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 176.Manzar H., Abdulhussein D., Yap T.E., Cordeiro M.F. Cellular Consequences of Coenzyme Q10 Deficiency in Neurodegeneration of the Retina and Brain. Int. J. Mol. Sci. 2020;21:9299. doi: 10.3390/ijms21239299. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 177.Johnson J., Mercado-Ayon E., Mercado-Ayon Y., Dong Y.N., Halawani S., Ngaba L., Lynch D.R. Mitochondrial Dysfunction in the Development and Progression of Neurodegenerative Diseases. Arch. Biochem. Biophys. 2021;702:108698. doi: 10.1016/j.abb.2020.108698. [DOI] [PubMed] [Google Scholar]
- 178.Zuo Y., Xie J., Li X., Li Y., Thirupathi A., Zhang J., Yu P., Gao G., Chang Y., Shi Z. Ferritinophagy-Mediated Ferroptosis Involved in Paraquat-Induced Neurotoxicity of Dopaminergic Neurons: Implication for Neurotoxicity in PD. Oxid. Med. Cell. Longev. 2021;2021:9961628. doi: 10.1155/2021/9961628. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 179.Mahoney-Sánchez L., Bouchaoui H., Ayton S., Devos D., Duce J.A., Devedjian J.-C. Ferroptosis and Its Potential Role in the Physiopathology of Parkinson’s Disease. Prog. Neurobiol. 2021;196:101890. doi: 10.1016/j.pneurobio.2020.101890. [DOI] [PubMed] [Google Scholar]
- 180.Moreau C., Duce J.A., Rascol O., Devedjian J.-C., Berg D., Dexter D., Cabantchik Z.I., Bush A.I., Devos D., FAIRPARK-II study group Iron as a Therapeutic Target for Parkinson’s Disease. Mov. Disord. Off. J. Mov. Disord. Soc. 2018;33:568–574. doi: 10.1002/mds.27275. [DOI] [PubMed] [Google Scholar]
- 181.Arenas-Jal M., Suñé-Negre J.M., García-Montoya E. Coenzyme Q10 Supplementation: Efficacy, Safety, and Formulation Challenges. Compr. Rev. Food Sci. Food Saf. 2020;19:574–594. doi: 10.1111/1541-4337.12539. [DOI] [PubMed] [Google Scholar]
- 182.Martin-Bastida A., Ward R.J., Newbould R., Piccini P., Sharp D., Kabba C., Patel M.C., Spino M., Connelly J., Tricta F., et al. Brain Iron Chelation by Deferiprone in a Phase 2 Randomised Double-Blinded Placebo Controlled Clinical Trial in Parkinson’s Disease. Sci. Rep. 2017;7:1398. doi: 10.1038/s41598-017-01402-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 183.University Hospital . Conservative Iron Chelation as a Disease-Modifying Strategy in Parkinson’s Disease. European Multicentre, Parallel-Group, Placebo-Controlled, Randomized Clinical Trial of Deferiprone. Clinicaltrials.gov; Lille, France: 2022. [Google Scholar]
- 184.FAIRPARK II|EU Funded Research Project|Parkinson’s Disease—Fair Park II (Fairpark2.Eu) [(accessed on 6 January 2023)]. Available online: http://fairpark2.eu/
- 185.Forni D.G.L. Ferrochelating Treatment in Patients Affected by “Neurodegeneration With Brain Iron Accumulation” (NBIA) Clinicaltrials.gov; Cagliari and Genoa, Italy: 2022. [Google Scholar]
- 186.Abbruzzese G., Cossu G., Balocco M., Marchese R., Murgia D., Melis M., Galanello R., Barella S., Matta G., Ruffinengo U., et al. A Pilot Trial of Deferiprone for Neurodegeneration with Brain Iron Accumulation. Haematologica. 2011;96:1708–1711. doi: 10.3324/haematol.2011.043018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 187.University Hospital . Conservative Iron Chelation as a Disease-Modifying Strategy in Amyotrophic Lateral Sclerosis: Multicentre, Parallel-Group, Placebo-Controlled, Randomized Clinical Trial of Deferiprone. Clinicaltrials.gov; Lille, France: 2022. [Google Scholar]
- 188.Llabani E., Hicklin R.W., Lee H.Y., Motika S.E., Crawford L.A., Weerapana E., Hergenrother P.J. Diverse Compounds from Pleuromutilin Lead to a Thioredoxin Inhibitor and Inducer of Ferroptosis. Nat. Chem. 2019;11:521–532. doi: 10.1038/s41557-019-0261-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 189.Chen P., Wu Q., Feng J., Yan L., Sun Y., Liu S., Xiang Y., Zhang M., Pan T., Chen X., et al. Erianin, a Novel Dibenzyl Compound in Dendrobium Extract, Inhibits Lung Cancer Cell Growth and Migration via Calcium/Calmodulin-Dependent Ferroptosis. Signal Transduct. Target. Ther. 2020;5:51. doi: 10.1038/s41392-020-0149-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 190.Song Z., Xiang X., Li J., Deng J., Fang Z., Zhang L., Xiong J. Ruscogenin Induces Ferroptosis in Pancreatic Cancer Cells. Oncol. Rep. 2020;43:516–524. doi: 10.3892/or.2019.7425. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 191.Fu F., Lai Q., Hu J., Zhang L., Zhu X., Kou J., Yu B., Li F. Ruscogenin Alleviates Myocardial Ischemia-Induced Ferroptosis through the Activation of BCAT1/BCAT2. Antioxidants. 2022;11:583. doi: 10.3390/antiox11030583. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 192.Hu M., An S. Ruscogenin Prevents Folic Acid-Induced Acute Kidney Damage by Inhibiting Rev-Erbα/β-Mediated Ferroptosis. Comput. Intell. Neurosci. 2022;2022:8066126. doi: 10.1155/2022/8066126. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 193.Chen T.-C., Chuang J.-Y., Ko C.-Y., Kao T.-J., Yang P.-Y., Yu C.-H., Liu M.-S., Hu S.-L., Tsai Y.-T., Chan H., et al. AR Ubiquitination Induced by the Curcumin Analog Suppresses Growth of Temozolomide-Resistant Glioblastoma through Disrupting GPX4-Mediated Redox Homeostasis. Redox Biol. 2019;30:101413. doi: 10.1016/j.redox.2019.101413. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 194.Li R., Zhang J., Zhou Y., Gao Q., Wang R., Fu Y., Zheng L., Yu H. Transcriptome Investigation and In Vitro Verification of Curcumin-Induced HO-1 as a Feature of Ferroptosis in Breast Cancer Cells. Oxid. Med. Cell. Longev. 2020;2020:3469840. doi: 10.1155/2020/3469840. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 195.Guerrero-Hue M., García-Caballero C., Palomino-Antolín A., Rubio-Navarro A., Vázquez-Carballo C., Herencia C., Martín-Sanchez D., Farré-Alins V., Egea J., Cannata P., et al. Curcumin Reduces Renal Damage Associated with Rhabdomyolysis by Decreasing Ferroptosis-Mediated Cell Death. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2019;33:8961–8975. doi: 10.1096/fj.201900077R. [DOI] [PubMed] [Google Scholar]
- 196.de Souza Farias S.A., da Costa K.S., Martins J.B.L. Analysis of Conformational, Structural, Magnetic, and Electronic Properties Related to Antioxidant Activity: Revisiting Flavan, Anthocyanidin, Flavanone, Flavonol, Isoflavone, Flavone, and Flavan-3-Ol. ACS Omega. 2021;6:8908–8918. doi: 10.1021/acsomega.0c06156. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 197.Perez C.A., Wei Y., Guo M. Iron-Binding and Anti-Fenton Properties of Baicalein and Baicalin. J. Inorg. Biochem. 2009;103:326–332. doi: 10.1016/j.jinorgbio.2008.11.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 198.Li Q., Li Q.-Q., Jia J.-N., Sun Q.-Y., Zhou H.-H., Jin W.-L., Mao X.-Y. Baicalein Exerts Neuroprotective Effects in FeCl3-Induced Posttraumatic Epileptic Seizures via Suppressing Ferroptosis. Front. Pharmacol. 2019;10:638. doi: 10.3389/fphar.2019.00638. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 199.Holland T.M., Agarwal P., Wang Y., Leurgans S.E., Bennett D.A., Booth S.L., Morris M.C. Dietary Flavonols and Risk of Alzheimer Dementia. Neurology. 2020;94:e1749–e1756. doi: 10.1212/WNL.0000000000008981. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 200.Yuan Y., Zhai Y., Chen J., Xu X., Wang H. Kaempferol Ameliorates Oxygen-Glucose Deprivation/Reoxygenation-Induced Neuronal Ferroptosis by Activating Nrf2/SLC7A11/GPX4 Axis. Biomolecules. 2021;11:923. doi: 10.3390/biom11070923. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 201.Li X., Zeng J., Liu Y., Liang M., Liu Q., Li Z., Zhao X., Chen D. Inhibitory Effect and Mechanism of Action of Quercetin and Quercetin Diels-Alder Anti-Dimer on Erastin-Induced Ferroptosis in Bone Marrow-Derived Mesenchymal Stem Cells. Antioxidants. 2020;9:205. doi: 10.3390/antiox9030205. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 202.Zheng K., Dong Y., Yang R., Liang Y., Wu H., He Z. Regulation of Ferroptosis by Bioactive Phytochemicals: Implications for Medical Nutritional Therapy. Pharmacol. Res. 2021;168:105580. doi: 10.1016/j.phrs.2021.105580. [DOI] [PubMed] [Google Scholar]
- 203.Quinn P.J., Boldyrev A.A., Formazuyk V.E. Carnosine: Its Properties, Functions and Potential Therapeutic Applications. Mol. Asp. Med. 1992;13:379–444. doi: 10.1016/0098-2997(92)90006-L. [DOI] [PubMed] [Google Scholar]
- 204.Pan M., Liu K., Yang J., Liu S., Wang S., Wang S. Advances on Food-Derived Peptidic Antioxidants—A Review. Antioxidants. 2020;9:799. doi: 10.3390/antiox9090799. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 205.Sarmadi B.H., Ismail A. Antioxidative Peptides from Food Proteins: A Review. Peptides. 2010;31:1949–1956. doi: 10.1016/j.peptides.2010.06.020. [DOI] [PubMed] [Google Scholar]
- 206.Coda R., Rizzello C.G., Pinto D., Gobbetti M. Selected Lactic Acid Bacteria Synthesize Antioxidant Peptides during Sourdough Fermentation of Cereal Flours. Appl. Environ. Microbiol. 2012;78:1087–1096. doi: 10.1128/AEM.06837-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 207.Csire G., Canabady-Rochelle L., Averlant-Petit M.-C., Selmeczi K., Stefan L. Both Metal-Chelating and Free Radical-Scavenging Synthetic Pentapeptides as Efficient Inhibitors of Reactive Oxygen Species Generation. Metallomics. 2020;12:1220–1229. doi: 10.1039/d0mt00103a. [DOI] [PubMed] [Google Scholar]
- 208.Yan Q.-J., Huang L.-H., Sun Q., Jiang Z.-Q., Wu X. Isolation, Identification and Synthesis of Four Novel Antioxidant Peptides from Rice Residue Protein Hydrolyzed by Multiple Proteases. Food Chem. 2015;179:290–295. doi: 10.1016/j.foodchem.2015.01.137. [DOI] [PubMed] [Google Scholar]
- 209.Jiang Y., Zhang M., Lin S., Cheng S. Contribution of Specific Amino Acid and Secondary Structure to the Antioxidant Property of Corn Gluten Proteins. Food Res. Int. Ott. Ont. 2018;105:836–844. doi: 10.1016/j.foodres.2017.12.022. [DOI] [PubMed] [Google Scholar]
- 210.Agrawal H., Joshi R., Gupta M. Isolation, Purification and Characterization of Antioxidative Peptide of Pearl Millet (Pennisetum glaucum) Protein Hydrolysate. Food Chem. 2016;204:365–372. doi: 10.1016/j.foodchem.2016.02.127. [DOI] [PubMed] [Google Scholar]
- 211.Xia Y., Bamdad F., Gänzle M., Chen L. Fractionation and Characterization of Antioxidant Peptides Derived from Barley Glutelin by Enzymatic Hydrolysis. Food Chem. 2012;134:1509–1518. doi: 10.1016/j.foodchem.2012.03.063. [DOI] [PubMed] [Google Scholar]
- 212.Zhang S.B., Wang Z., Xu S.Y., Gao X.F. Purification and Characterization of a Radical Scavenging Peptide from Rapeseed Protein Hydrolysates. J. Am. Oil Chem. Soc. 2009;86:959–966. doi: 10.1007/s11746-009-1404-5. [DOI] [Google Scholar]
- 213.Chen N., Yang H., Sun Y., Niu J., Liu S. Purification and Identification of Antioxidant Peptides from Walnut (Juglans regia L.) Protein Hydrolysates. Peptides. 2012;38:344–349. doi: 10.1016/j.peptides.2012.09.017. [DOI] [PubMed] [Google Scholar]
- 214.Yang R., Li X., Lin S., Zhang Z., Chen F. Identification of Novel Peptides from 3 to 10kDa Pine Nut (Pinus koraiensis) Meal Protein, with an Exploration of the Relationship between Their Antioxidant Activities and Secondary Structure. Food Chem. 2017;219:311–320. doi: 10.1016/j.foodchem.2016.09.163. [DOI] [PubMed] [Google Scholar]
- 215.Shen S., Chahal B., Majumder K., You S.-J., Wu J. Identification of Novel Antioxidative Peptides Derived from a Thermolytic Hydrolysate of Ovotransferrin by LC-MS/MS. J. Agric. Food Chem. 2010;58:7664–7672. doi: 10.1021/jf101323y. [DOI] [PubMed] [Google Scholar]
- 216.Yousr M., Howell N. Antioxidant and ACE Inhibitory Bioactive Peptides Purified from Egg Yolk Proteins. Int. J. Mol. Sci. 2015;16:29161–29178. doi: 10.3390/ijms161226155. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 217.Huang W.-Y., Majumder K., Wu J. Oxygen Radical Absorbance Capacity of Peptides from Egg White Protein Ovotransferrin and Their Interaction with Phytochemicals. Food Chem. 2010;123:635–641. doi: 10.1016/j.foodchem.2010.04.083. [DOI] [Google Scholar]
- 218.Najafian L., Babji A.S. Isolation, Purification and Identification of Three Novel Antioxidative Peptides from Patin (Pangasius sutchi) Myofibrillar Protein Hydrolysates. LWT-Food Sci. Technol. 2015;60:452–461. doi: 10.1016/j.lwt.2014.07.046. [DOI] [Google Scholar]
- 219.Guo L., Hou H., Li B., Zhang Z., Wang S., Zhao X. Preparation, Isolation and Identification of Iron-Chelating Peptides Derived from Alaska Pollock Skin. Process Biochem. 2013;48:988–993. doi: 10.1016/j.procbio.2013.04.013. [DOI] [Google Scholar]
- 220.Bordbar S., Ebrahimpour A., Zarei M., Abdul Hamid A., Saari N. Alcalase-Generated Proteolysates of Stone Fish (Actinopyga lecanora) Flesh as a New Source of Antioxidant Peptides. Int. J. Food Prop. 2018;21:1541–1559. doi: 10.1080/10942912.2018.1497060. [DOI] [Google Scholar]
- 221.Kim S.S., Ahn C.-B., Moon S.W., Je J.-Y. Purification and Antioxidant Activities of Peptides from Sea Squirt (Halocynthia roretzi) Protein Hydrolysates Using Pepsin Hydrolysis. Food Biosci. 2018;25:128–133. doi: 10.1016/j.fbio.2018.08.010. [DOI] [Google Scholar]
- 222.Gallego M., Mora L., Reig M., Toldrá F. Stability of the Potent Antioxidant Peptide SNAAC Identified from Spanish Dry-Cured Ham. Food Res. Int. 2018;105:873–879. doi: 10.1016/j.foodres.2017.12.006. [DOI] [PubMed] [Google Scholar]
- 223.Escudero E., Mora L., Fraser P.D., Aristoy M.-C., Toldrá F. Identification of Novel Antioxidant Peptides Generated in Spanish Dry-Cured Ham. Food Chem. 2013;138:1282–1288. doi: 10.1016/j.foodchem.2012.10.133. [DOI] [PubMed] [Google Scholar]
- 224.Xing L.-J., Hu Y.-Y., Hu H.-Y., Ge Q.-F., Zhou G.-H., Zhang W.-G. Purification and Identification of Antioxidative Peptides from Dry-Cured Xuanwei Ham. Food Chem. 2016;194:951–958. doi: 10.1016/j.foodchem.2015.08.101. [DOI] [PubMed] [Google Scholar]
- 225.Zhu C.-Z., Zhang W.-G., Zhou G.-H., Xu X.-L., Kang Z.-L., Yin Y. Isolation and Identification of Antioxidant Peptides from Jinhua Ham. J. Agric. Food Chem. 2013;61:1265–1271. doi: 10.1021/jf3044764. [DOI] [PubMed] [Google Scholar]
- 226.Zhang Q., Tong X., Li Y., Wang H., Wang Z., Qi B., Sui X., Jiang L. Purification and Characterization of Antioxidant Peptides from Alcalase-Hydrolyzed Soybean (Glycine max L.) Hydrolysate and Their Cytoprotective Effects in Human Intestinal Caco-2 Cells. J. Agric. Food Chem. 2019;67:5772–5781. doi: 10.1021/acs.jafc.9b01235. [DOI] [PubMed] [Google Scholar]
- 227.Wen C., Zhang J., Feng Y., Duan Y., Ma H., Zhang H. Purification and Identification of Novel Antioxidant Peptides from Watermelon Seed Protein Hydrolysates and Their Cytoprotective Effects on H2O2-Induced Oxidative Stress. Food Chem. 2020;327:127059. doi: 10.1016/j.foodchem.2020.127059. [DOI] [PubMed] [Google Scholar]
- 228.Hu X.-M., Wang Y.-M., Zhao Y.-Q., Chi C.-F., Wang B. Antioxidant Peptides from the Protein Hydrolysate of Monkfish (Lophius litulon) Muscle: Purification, Identification, and Cytoprotective Function on HepG2 Cells Damage by H2O2. Mar. Drugs. 2020;18:153. doi: 10.3390/md18030153. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 229.Wang J., Liao W., Nimalaratne C., Chakrabarti S., Wu J. Purification and Characterization of Antioxidant Peptides from Cooked Eggs Using a Dynamic in Vitro Gastrointestinal Model in Vascular Smooth Muscle A7r5 Cells. NPJ Sci. Food. 2018;2:7. doi: 10.1038/s41538-018-0015-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 230.Wu J., Sun B., Luo X., Zhao M., Zheng F., Sun J., Li H., Sun X., Huang M. Cytoprotective Effects of a Tripeptide from Chinese Baijiu against AAPH-Induced Oxidative Stress in HepG2 Cells via Nrf2 Signaling. RSC Adv. 2018;8:10898–10906. doi: 10.1039/C8RA01162A. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 231.Jiang N., Zhang S., Zhu J., Shang J., Gao X. Hypoglycemic, Hypolipidemic and Antioxidant Effects of Peptides from Red Deer Antlers in Streptozotocin-Induced Diabetic Mice. Tohoku J. Exp. Med. 2015;236:71–79. doi: 10.1620/tjem.236.71. [DOI] [PubMed] [Google Scholar]
- 232.Ben Khaled H., Ghlissi Z., Chtourou Y., Hakim A., Ktari N., Fatma M.A., Barkia A., Sahnoun Z., Nasri M. Effect of Protein Hydrolysates from Sardinelle (Sardinella aurita) on the Oxidative Status and Blood Lipid Profile of Cholesterol-Fed Rats. Food Res. Int. 2012;45:60–68. doi: 10.1016/j.foodres.2011.10.003. [DOI] [Google Scholar]
- 233.Zou Z., Wang M., Wang Z., Aluko R.E., He R. Antihypertensive and Antioxidant Activities of Enzymatic Wheat Bran Protein Hydrolysates. J. Food Biochem. 2020;44:e13090. doi: 10.1111/jfbc.13090. [DOI] [PubMed] [Google Scholar]
- 234.Ding J.-F., Li Y.-Y., Xu J.-J., Su X.-R., Gao X., Yue F.-P. Study on Effect of Jellyfish Collagen Hydrolysate on Anti-Fatigue and Anti-Oxidation. Food Hydrocoll. 2011;25:1350–1353. doi: 10.1016/j.foodhyd.2010.12.013. [DOI] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
No new data were created.