search button
Open Access

Ferroptosis in schizophrenia: Mechanisms and therapeutic potentials (Review)

  • Authors:
    • Shuang Lv
    • Chunxia Luo

  • View Affiliations

  • Published online on: November 22, 2024     https://doi.org/10.3892/mmr.2024.13402
  • Article Number: 37

  • Copyright: © Lv et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Schizophrenia, a complex psychiatric disorder, presents with multifaceted symptoms and important challenges in treatment, primarily due to its pathophysiological complexity, which involves oxidative stress and aberrant iron metabolism. Recent insights into ferroptosis, a unique form of iron‑dependent cell death characterized by lipid peroxidation and antioxidant system failures, open new avenues for understanding the neurobiological foundation of schizophrenia. The present review explores the interplay between ferroptosis and schizophrenia, emphasizing the potential contributions of disrupted iron homeostasis and oxidative mechanisms to the pathology and progression of this disease. The emerging evidence linking ferroptosis with the oxidative stress observed in schizophrenia provides a compelling narrative for re‑evaluating current therapeutic strategies and exploring novel interventions targeting these molecular pathways, such as the glutathione peroxidase 4 pathway and the ferroptosis suppressor protein 1 pathway. By integrating recent advances in ferroptosis research, the current review highlights innovative therapeutic potentials, including N‑acetylcysteine, selenium, omega‑3 fatty acids and iron chelation therapy, which could address the limitations of existing treatments and improve clinical outcomes for individuals with schizophrenia.

Introduction

Schizophrenia, a multifaceted psychiatric condition, affects ~287 per 100,000 individuals globally (1), presenting important challenges due to its diverse symptoms and effects on brain functionality. This disorder is characterized by three primary categories of symptoms: i) Positive symptoms, including hallucinations (predominantly auditory) and delusions (2,3); ii) negative symptoms, which comprise emotional numbness, apathy and social isolation (4,5); and iii) cognitive symptoms, which disrupt daily functioning by impairing memory, attention and executive skills (6). A total of >50% of patients with chronic schizophrenia experience at least one negative symptom (7). These symptoms do not tend to improve spontaneously throughout the progression of the disease and about one-third of patients demonstrate a poor response to the antipsychotics commonly used today, such as Chlorpromazine (8,9). The typical onset of schizophrenia varies by sex, with men usually developing the disorder between the ages of 18 and 25 years, whereas women tend to have a later onset, typically between 25 and 35 years (10). Schizophrenia evolves through various stages: i) The prodromal phase, marked by initial symptoms and a decline in brain function (11); ii) the acute phase, characterized by intense psychotic symptoms and significant functional degradation (12); and iii) the residual phase, during which some symptoms may abate but substantial functional difficulties persist (13,14). Treatment of schizophrenia involves both medications and psychosocial interventions (15). Medication includes primarily antipsychotic drugs that target dopamine receptors in the brain, which can alleviate positive symptoms, such as hallucination and delusions (16). Alongside medication, therapies like cognitive behavioral therapy aid the change of harmful thought patterns (17), while family-oriented interventions, such as psychoeducation and mutual support among families of schizophrenia patients, can notably enhance the patients' treatment satisfaction and adherence (18). Additional options such as electroconvulsive therapy may be used for severe cases (19). A comprehensive care approach, integrating these treatments, is crucial for the effective management of schizophrenia.

Ferroptosis is a distinct form of programmed cell death dependent on iron and characterized by the lethal accumulation of lipid peroxides (20). In contrast to other cell death mechanisms, such as apoptosis or necrosis, ferroptosis is predominantly caused by failure of the cellular antioxidant systems, particularly the enzyme glutathione peroxidase 4 (GPX4) (21,22). This enzyme normally detoxifies lipid peroxides by catalyzing the transformation of lipid hydroperoxides into harmless lipid alcohols, using glutathione (GSH) as a reducing agent. This action is crucial in maintaining the integrity of cellular membranes and preventing oxidative damage leading to ferroptosis (23). Researchers have also identified mechanisms of ferroptosis that do not depend on GPX4, and a major component of this GPX4-independent pathway is ferroptosis suppressor protein 1 (FSP1) (24). FSP1 uses NADPH to catalyze the reduction of coenzyme Q10 (CoQ10), a potent lipophilic antioxidant. This reduction is vital to prevent the accumulation of lipid peroxides (25). From a morphological perspective, cells undergoing ferroptosis demonstrate several distinctive alterations (26). Electron microscopy reveals that these cells typically have smaller mitochondria with denser membranes. Furthermore, the mitochondria often exhibit a loss of cristae and may show ruptures in their outer membranes (20,27,28). Changes in the cellular membrane, including increased density and notable damage, also occur, culminating in the disruption of cellular integrity and eventual death (29,30). This pathway of cell death is intricately connected to various metabolic functions within the cell, such as lipid metabolism, iron regulation and the management of reactive oxygen species (ROS), underscoring its important impact on cellular health and disease pathogenesis (31–33). Ferroptosis has been implicated in a range of diseases, such as cancer (34) and neurodegenerative conditions (35), where iron dysregulation and oxidative stress are prominent.

The interconnection between ferroptosis and schizophrenia is attracting considerable attention, triggered by the pervasive role of oxidative stress and anomalies in iron metabolism observed in schizophrenia (36,37). Oxidative stress, a well-documented aspect of schizophrenia, is linked to both the pathogenesis of the disorder and the degeneration of neural circuits (38). Ferroptosis, with its fundamental role in managing iron levels and oxidative responses (39), offers a compelling framework to explore how disruptions in these cellular mechanisms may contribute to the developmental and progressive phases of schizophrenia. Examining the biochemical processes underlying ferroptosis, such as iron accumulation, lipid peroxide formation and antioxidant system failures, in alignment with the pathophysiological traits of schizophrenia, could reveal potential contributions of ferroptosis to the onset and progression of this disorder. Additionally, insights into ferroptosis could lead to innovative therapeutic strategies, potentially addressing the limitations of current treatments by targeting the underlying cellular disturbances in schizophrenia.

Ferroptosis: Mechanisms and indicators

Iron metabolism and accumulation of iron

Iron is essential for various biological processes, including oxygen transport, DNA synthesis and electron transfer, due to its ability to exist in multiple oxidation states (40). The cellular uptake of iron is primarily facilitated through the binding of transferrin-bound iron to transferrin receptors, which internalize the iron into cells (41). Once inside the cells, iron is released from transferrin in acidic endosomes and then distributed into the labile iron pool (LIP), readily participating in critical cellular functions or being stored in ferritin (42,43). Most of the intracellular iron is sequestered in ferritin, where it is stored in a less reactive ferric iron state, helping to stabilize the balance with the volatile LIP (44). This storage mechanism is key, especially in the brain, where specific cells, such as oligodendrocytes, microglia and neurons, express ferritin (45–48), highlighting its role in preserving neural integrity and guarding against oxidative damage. Under conditions of stress or specific cellular signals, ferritin can undergo degradation via a process called ferritinophagy, typically facilitated by nuclear receptor coactivator 4 (NCOA4) (49). This degradation liberates iron back into the LIP, enhancing the availability of ferrous iron that can initiate the production of harmful lipid peroxides, thereby triggering the pathway of ferroptosis (50,51). The export of iron from cells is controlled by ferroportin, the sole known cellular iron exporter (52). The activity of ferroportin is stringently regulated by hepcidin, a hormone produced in the liver (53). Hepcidin binds to ferroportin, inducing its internalization and degradation, which diminishes iron export, and can result in an accumulation of intracellular iron if overexpressed or when mutations impede the function of ferroportin (50,54).

Propagation of lipid peroxidation

Lipid peroxidation is both a marker and mediator of ferroptosis (26). This biochemical process begins when ROS, particularly hydroxyl radicals (•OH), interact with the polyunsaturated fatty acids (PUFAs) in the phospholipid bilayer of cell membranes (55,56). Iron, through the Fenton reaction, catalyzes the conversion of hydrogen peroxide (H2O2) into •OH (57,58). These radicals are highly reactive and can abstract hydrogen atoms from the carbon atoms at the bis-allylic positions in PUFAs (59). This abstraction creates lipid radicals, initiating the lipid peroxidation chain reaction. Once initiated, the lipid radicals react with oxygen to form lipid peroxyl radicals, which are even more reactive (60). These radicals then abstract hydrogen from adjacent lipid molecules, propagating the chain reaction across the membrane, thereby spreading the oxidative damage extensively (61,62).

This chain reaction progresses until two lipid peroxyl radicals react, thus terminating the process. However, several reactive aldehydes, such as 4-hydroxynonenal (4-HNE) and malondialdehyde, are produced during this phase (63,64). These compounds can form adducts with DNA, proteins and other vital macromolecules, further impairing cellular functions (65–67). For instance, in the brain tissue of patients with Alzheimer's disease, the peroxidation product 4-HNE can bind covalently to critical neuronal mitochondrial, membrane and cytosolic proteins via Michael addition reactions. This binding results in functional impairments of important neuronal proteins, such as glyceraldehyde-3-phosphate dehydrogenase and α-enolase, leading to neuronal death and consequent cognitive decline (68). Moreover, lipid peroxidation involves feedback mechanisms that exacerbate damage. Released iron from damaged proteins or mitochondria can catalyze additional Fenton reactions, perpetuating the cycle of ROS production and lipid peroxidation (69). This feedback loop is particularly harmful in environments with elevated iron levels or compromised antioxidant defenses.

In the neurological context of schizophrenia, the susceptibility of the brain to lipid peroxidation is important due to its high lipid content and metabolic activity, coupled with relatively low antioxidant protection (36,70,71). Schizophrenia may be exacerbated by anomalies in iron metabolism and antioxidant pathways, thereby increasing susceptibility to oxidative damage, which is linked to the cognitive and behavioral manifestations observed in schizophrenia (72,73).

Promotion and amplification mechanisms of ferroptosis

The intricate interplay of various cellular mechanisms contributes to the initiation and amplification of ferroptosis, particularly within the neural contexts relevant to schizophrenia. Mainly the NCOA4-, NADPH oxidase 4 (NOX4)-, activating transcription factor 3 (ATF3)-and p53-mediated mechanisms are crucial in modulating iron metabolism, lipid peroxidation and antioxidant defenses, thereby affecting the vulnerability to ferroptosis under physiological and pathological conditions (Fig. 1).

Figure 1.

Major mechanisms that promote or inhibit ferroptosis. NCOA4 binds to ferritin and transports it to the autophagosome. The mature autophagosome then fuses with the lysosome, leading to the degradation of ferritin and the release of stored Fe2+. NOX4 catalyzes the reduction of O2 to H2O2. Fe2+ reacts with H2O2 in the Fenton reaction to produce •OH, which then promote ferroptosis. ATF3 enhances the expression of genes such as ACSL4 and LOXs, thereby promoting lipid peroxidation. System xc−, a cystine/glutamate antiporter composed of the subunits SLC7A11 and SLC3A2, imports cystine into cells in exchange for the export of glutamate. Inside the cell, cystine is reduced to cysteine, which then participates in the synthesis of GSH. The enzyme GPX4 catalyzes the conversion of GSH into its oxidized form, GSSG, which inhibits ferroptosis. p53 upregulates the expression of SAT1 and GLS2, leading to the production of ROS and promoting ferroptosis. In addition, p53 facilitates ferroptosis by decreasing the expression of SLC7A11, which impairs cystine import and lowers GSH levels. p53 regulates ferroptosis in both directions. While it can promote ferroptosis, p53 also inhibits ferroptosis by increasing the expression of GCLC and GCLM, which are important for GSH synthesis. Additionally, p53 suppresses ferroptosis by promoting p21 expression, which functions as an antioxidant. DHODH is an enzyme in the mitochondria that converts dihydroorotate into orotate. This conversion also reduces CoQ to CoQH2, which can inhibit the production of PLOO· that promote ferroptosis. FMN and its reduced form, FMNH2, participate in the process by transferring electrons needed for these reactions. GCH1 converts GTP into BH4, which is then recycled back from its oxidized form, BH2, with the help of DHFR using NAD(P)H. BH4 and αTOH work together to prevent lipid peroxidation, effectively blocking ferroptosis. NCOA4, nuclear receptor coactivator 4; Fe2+, ferrous iron; Fe3+, ferric iron; NOX4, NADPH oxidase 4; H2O2, hydrogen peroxide; •OH, hydroxyl radicals; ATF3, activating transcription factor 3; ACSL4, acyl-CoA synthetase long chain family member 4; LOX lipoxygenase; SAT1, spermidine/spermine N1-acetyltransferase 1; GLS2, glutaminase 2; ROS, reactive oxygen species; SLC7A11, solute carrier family 7 member 11; SLC3A2, solute carrier family 3 member 2; GSH, glutathione; GPX4, glutathione peroxidase 4; GSSG, glutathione disulfide; GCLC, glutamate-cysteine ligase catalytic subunit; GCLM, glutamate-cysteine ligase modifier subunit; DHODH, dihydroorotate dehydrogenase; CoQ, coenzyme Q; PLOO·, peroxyl radicals; FMN, flavin mononucleotide; GCH1, GTP cyclohydrolase-1; BH4, tetrahydrobiopterin; BH2, dihydrobiopterin; MTX, Methotrexate; DHFR, dihydrofolate reductase; αTOH, α-tocopherol; FSP1, ferroptosis suppressor protein 1.

NCOA4-mediated promotion mechanism

NCOA4 is important in various cellular processes, surpassing its originally identified role as a coactivator for nuclear receptors, such as androgen and thyroid hormone receptors (74,75). By interacting with these receptors, NCOA4 promotes their transcriptional activities, aided by its ability to recruit additional transcriptional machinery (76). The functions of NCOA4 are attributed to its structural design, comprising an N-terminal domain that facilitates protein-protein interactions, a central coactivator domain essential for its coactivation role and a C-terminal domain crucial for the autophagic breakdown of ferritin (76–79).

NCOA4 has an essential function in iron metabolism, which is crucial for the proper maintenance of cellular iron balance (49,80,81). NCOA4 is highly expressed in critical organs involved in iron regulation, such as the liver, bone marrow and spleen (82,83). The involvement of NCOA4 in ferritinophagy underscores its capability to regulate iron storage and mobilization effectively (84). In conditions of iron sufficiency, NCOA4 is degraded to prevent excessive ferritinophagy, thereby avoiding iron overload that can exacerbate oxidative stress and cellular damage (79,85,86). Conversely, under conditions of iron deficiency or cellular stress, NCOA4 levels increase to promote ferritin degradation and maintain essential iron supply for metabolic processes (81,87,88). This regulatory mechanism ensures that ferritinophagy mediated by NCOA4 adapts to the cellular iron status and environmental cues, maintaining iron homeostasis and shielding cells from oxidative stress due to uncontrolled iron release.

NCOA4 is primarily regulated at the post-translational level, involving dual degradation pathways: Autophagy, particularly through its role in ferritinophagy (79,84), and proteasomal degradation, which is facilitated by the E3 ubiquitin-protein ligase HERC2 under iron-replete conditions (79). This degradation is further fine-tuned by ferritin levels. Knockout of ferritin heavy chain 1 (FTH1) has been demonstrated to reduce NCOA4 levels by increasing free iron, which activates the HERC2-mediated degradation of NCOA4 (79,89). Conversely, overexpression of FTH1 can lead to NCOA4 accumulation, indicating a protective sequestration from degradation pathways (89). This regulation can alter the interaction of NCOA4 with ferritin, potentially leading to its degradation and influencing the efficacy of ferritinophagy. Additionally, NCOA4 engages with autophagy components, such as microtubule-associated protein 1A/1B-light chain 3, which are integral to autophagosome assembly and the selective autophagic degradation of ferritin (49,90,91). This complex regulatory framework ensures that the activity of NCOA4 is finely adjusted according to the internal iron conditions, effectively responding to changes and protecting against iron-related oxidative stress.

NOX4-mediated promotion mechanism

The NOX enzyme family, encompassing seven isoforms (NOX1 to NOX5, DUOX1 and DUOX2), is pivotal for generating ROS, which are integral to cellular signaling, host defense and redox balance maintenance (92,93). Each isoform has specific tissue distributions, regulatory mechanisms and functional roles, thus contributing uniquely to cellular functions (94).

NOX4 is particularly notable within the NOX family for its intrinsic activity without the need for cytosolic subunits required by other isoforms, such as NOX1, NOX2 and NOX3 (95,96). This unique attribute of NOX4 allows it to maintain a consistent production of H2O2 rather than superoxide, which is more commonly produced by its counterparts (97–99). This ability to generate H2O2, which is capable of diffusing across membranes and acting as a signaling molecule, implies a role for NOX4 in cellular signaling and regulation (100).

In the context of ferroptosis, the involvement of NOX4 in the continuous production of H2O2 is critical. In the presence of free iron, H2O2 is converted into highly reactive •OH via the Fenton reaction (101–103). These radicals are potent inducers of lipid peroxidation, leading to the oxidative breakdown of PUFAs within cellular membranes, which is a hallmark of ferroptosis (104,105). Moreover, the activity of NOX4 further intersects with iron metabolism, thereby modulating the ferroptotic process (106). For example, NOX4 affects the expression of ferritin, thus controlling the availability of free iron necessary for lipid peroxidation, and influences the formation of iron-sulfur clusters essential for numerous cellular enzymes, including aconitase and mitochondrial respiratory chain complexes (107,108).

Pharmacological interventions through the use of NOX inhibitors, including diphenyleneiodonium and GKT137831, have demonstrated that inhibiting NOX4 can substantially reduce ROS levels and lipid peroxidation, and thus protect against ferroptosis (109,110). These findings are further corroborated by experimental models that show increased NOX4 activity under oxidative stress conditions, including treatment with RAS-selective lethal small molecule 3 (RSL3) or erastin, which have been shown to enhance lipid peroxidation and subsequent cell death (111,112). This highlights the crucial role of NOX4 not only in inducing cellular oxidative stress but also in regulating iron-dependent cell death, indicating its importance in both normal physiological and pathological conditions.

ATF3-mediated promotion mechanism

ATF3, part of the ATF/cAMP-response element-binding protein family, is recognized as a stress-induced transcription factor critically affecting ferroptosis (113). ATF3 participates in various aspects of ferroptosis, influencing iron metabolism and lipid processing, and modifying cellular antioxidant defense mechanisms (114–116).

Directly, ATF3 facilitates ferroptosis by regulating genes that play vital roles in iron management and the initiation of lipid peroxidation (115,117). ATF3 upregulates heme oxygenase 1 that is integral in controlling internal iron levels conducive to lipid peroxidation (118). Additionally, ATF3 regulates genes such as acyl-CoA synthetase long chain family member 4 and lipoxygenases, essential for producing and incorporating PUFAs into cellular membranes, which is a critical step in lipid peroxidation (119–121).

Indirectly, ATF3 undermines cellular antioxidant defense mechanisms and promotes ferroptosis by downregulating components of the GSH pathway and system xc−, which safeguard cells against oxidative damage (113). Specifically, ATF3 reduces the expression of GPX4, which is crucial for converting lipid hydroperoxides into non-toxic compounds, thus promoting lipid peroxidation (115). Furthermore, the interactions of ATF3 with other stress-responsive transcription factors, such as NF-κB and p53, alter their regulatory activities, enhancing conditions that favor oxidative stress and ferroptosis (122–126). These interactions, especially with p53, may intensify pro-oxidant functions, thereby increasing the likelihood of ferroptosis under stress conditions (113,123).

p53-mediated bidirectional regulatory mechanism

The tumor suppressor protein p53 intricately regulates cell fate through its dual role in promoting and inhibiting ferroptosis (127,128). p53 facilitates ferroptosis by diminishing antioxidant defenses and elevating oxidative stress. p53 suppresses the expression of solute carrier family 7 member 11 (SLC7A11), a critical component of the system xc− cystine/glutamate antiporter necessary for cystine importation into cells (129). Cystine is transformed into cysteine, a precursor of GSH, which is crucial for detoxifying lipid peroxides (130). By lowering GSH levels, p53 increases the cellular vulnerability to oxidative stress and ferroptosis (129). Additionally, p53 increases the expression of spermidine/spermine N1-acetyltransferase 1 (SAT1), which leads to the acetylation of polyamines, thus reducing their antioxidant activity and elevating acetyl polyamine levels, which contribute to ROS production (128,131). Furthermore, p53 stimulates glutaminase 2 (GLS2) expression, enhancing the conversion of glutamine to glutamate, which increases ROS levels through the tricarboxylic acid cycle, thereby creating conditions conducive to ferroptosis (132,133).

Conversely, p53 also activates pathways that enhance the cellular antioxidant capabilities to counteract ferroptosis. p53 promotes CDKN1A gene transcription (coding for p21), which is known for regulating the cell cycle (134,135). However, p21 also affects the cellular antioxidant response, possibly by altering the stability and function of nuclear factor erythroid 2-related factor 2 (NRF2), which is a key regulator of antioxidant genes (136,137). This action enhances the cell ability to counteract oxidative stress and avert lipid peroxidation (138). p53 also promotes the expression of genes essential for synthesizing and recycling GSH, including glutamate-cysteine ligase modifier subunit (GCLM) and glutamate-cysteine ligase catalytic subunit (GCLC), as well as those involved in restoring oxidized GSH to its reduced state (139–141). These mechanisms demonstrate the comprehensive regulatory abilities of p53, enabling precise control over cell responses to stress signals, and switching between promoting and preventing ferroptosis depending on the cellular conditions.

Failure of cellular defense mechanisms

The disruption of cellular defense mechanisms against ferroptosis underscores the pathological processes observed in schizophrenia. Specifically, the GPX4-, FSP1-, dihydroorotate dehydrogenase (DHODH)- and GCH1-mediated mechanisms are crucial in safeguarding neural cells from oxidative stress and lipid peroxidation. The impairment of these defense mechanisms increases the susceptibility to ferroptosis, highlighting potential therapeutic targets (Fig. 1).

GPX4-mediated defense mechanism

GPX4 is a critical enzyme in mitigating oxidative stress by specifically targeting lipid peroxidation, which is a pivotal trigger of ferroptosis (22). GPX4 uses GSH as a reducing substrate to transform lipid hydroperoxides into lipid alcohols (142). This crucial reaction occurs at the active site of GPX4, distinguished by the presence of a selenocysteine residue that is vital for its activity (143). By limiting the accumulation of lipid peroxides, GPX4 contributes to maintaining the structural integrity of cellular membranes and preventing cell death (144).

GPX4 engages directly with lipid hydroperoxides found in cellular membranes or lipoproteins (144,145). By reducing the levels of these hydroperoxides, GPX4 inhibits the formation of more reactive and damaging lipid radicals, particularly protecting cells with membranes rich in PUFAs, which are highly susceptible to peroxidation (143,146). Furthermore, GPX4 extends its influence to regulate various signaling pathways that control cell proliferation and apoptosis, highlighting its broad functional implications beyond its antioxidant capabilities (144,147). GPX4 primarily regulates cell proliferation by inhibiting ferroptosis. Additionally, it acts as an anti-apoptotic factor by preventing the release of cytochrome C, inactivating caspase-3 and reducing hydroperoxide production, thus preventing mitochondrial apoptosis (144,147).

Ferroptosis is tightly linked to the disruption of cellular antioxidant defenses, notably through mechanisms impacting GPX4 (22). Central to this process are two primary factors: i) The depletion of GSH, which is critical for the antioxidant function of GPX4 (111); and ii) direct effects on GPX4, including oxidative damage to its structure, genetic alterations affecting its expression and functionality and the use of specific pharmacological inhibitors (148–150). Depletion of GSH due to intensified oxidative stress or the action of inhibitors significantly reduces the ability of GPX4 to counteract lipid peroxidation, leading to increased lipid peroxides and subsequent ferroptosis (151). Similarly, any direct disablement of GPX4 removes the critical barrier against lipid peroxidation, thereby inducing cell death via ferroptosis (149,150).

FSP1-mediated defense mechanism

Originally identified as apoptosis-inducing factor (AIF) mitochondria-associated 2 due to its resemblance to AIF, FSP1 has since been characterized through detailed studies as playing a crucial role in preventing ferroptosis rather than facilitating apoptosis (24,152). The FSP1 gene, located on human chromosome 10, encodes a protein comprising ~373 amino acids, including a flavin adenine dinucleotide (FAD)-binding motif critical for its enzymatic activity (153–155).

The enzymatic function of FSP1 is uniquely characterized by its ability to reduce CoQ10 to ubiquinol within the lipid bilayers of cell membranes via its FAD-binding domain (24,25). CoQ10, a lipid-soluble component of the electron transport chain that is prevalent in cellular membranes, serves as an electron carrier (156). The transformation of CoQ10 to ubiquinol by FSP1 markedly reinforces the cellular antioxidant capacity by providing ubiquinol (24,25), a powerful lipophilic antioxidant that captures lipid peroxyl radicals and prevents the peroxidation of PUFAs within the cell membranes (157).

Functioning independently from the traditional GSH-dependent antioxidant pathways, which are central to most cellular defense mechanisms against oxidative stress, FSP1 is instrumental in the inhibition of ferroptosis by directly limiting lipid peroxidation (24,25). The reduction of CoQ10 to ubiquinol not only impedes the onset but also the propagation of lipid peroxidation processes in the membranes (157,158). By neutralizing lipid peroxyl radicals produced when ROS interact with PUFAs, ubiquinol interrupts the lipid peroxidation chain reaction, thereby maintaining cellular integrity and function (159–161). This distinct role positions FSP1 as an essential, non-traditional regulator of ferroptosis.

DHODH-mediated defense mechanism

DHODH is an essential mitochondrial enzyme strategically positioned on the outer surface of the inner mitochondrial membrane (162). DHODH comprises two distinct domains: An α/β barrel domain that extends into the mitochondrial matrix and a larger domain anchored to the membrane, which houses the binding sites for the substrate dihydroorotate and the coenzyme flavin mononucleotide (163–166). This structural arrangement is crucial as it enables the direct transfer of electrons from dihydroorotate to the mitochondrial respiratory chain, specifically to CoQ10 (167). This connection bridges the synthesis of pyrimidines with mitochondrial electron transport.

DHODH is central to the de novo pyrimidine synthesis pathway, catalyzing the conversion of dihydroorotate to orotate as a crucial step, which is the only reaction within this pathway involving a mitochondrial enzyme (168). This process is indispensable for the synthesis of nucleotides that are critical for cell proliferation and growth regulation (169,170).

Beyond its primary biochemical functions, DHODH impacts cellular redox homeostasis and the process of ferroptosis (171). The inhibition of DHODH by brequinar disrupts mitochondrial electron flow, resulting in an increase in ROS. This increase in ROS enhances lipid peroxidation, which is a critical marker of ferroptosis (171,172). Furthermore, the inhibition of DHODH also reduces the levels of vital antioxidants, such as GSH, which are necessary for counteracting lipid peroxides, thus rendering cells more prone to oxidative stress and lipid damage (173,174). Therefore, DHODH has emerged as a potential regulatory hub, where its inhibition may enhance ferroptotic cell death, offering a novel angle for therapeutic intervention, particularly in cancers such as pancreatic adenocarcinoma (175) and breast cancer (176), where certain cells show resistance to other forms of cell death (171,177).

GCH1-mediated defense mechanism

GTP cyclohydrolase-1 (GCH1) is the rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin (BH4), a critical cofactor necessary for various biochemical processes, including the synthesis of monoamine neurotransmitters and the regulation of nitric oxide levels (178,179). GCH1 catalyzes the conversion of GTP to formic acid and dihydroneopterin triphosphate, the initial and rate-limiting step in BH4 synthesis (180,181). Following this, BH4 can be recycled back from its oxidized form, dihydrobiopterin, with the help of dihydrofolate reductase using NAD(P)H (182,183). Structurally, GCH1 is organized into a homodecameric formation, comprising two pentameric rings aligned into a toroidal configuration, with each monomer possessing a catalytic domain essential for the activity of GCH1 (184).

Previous studies have identified a significant role for GCH1 in regulating oxidative stress and its potential influence on ferroptosis (185,186). As an antioxidant, BH4, the enzymatic product of GCH1, effectively neutralizes ROS and reactive nitrogen species (187,188). This function is pivotal in preventing the uncoupling of nitric oxide synthase, which can elevate oxidative stress by shifting the production from nitric oxide to superoxide (189). BH4, along with α-tocopherol, which exhibits similar activity, enhances antioxidant capacities when used together. This combination shows a synergistic effect, significantly improving protection against lipid peroxidation compared to their individual use, and effectively blocking ferroptosis (190). The ability of GCH1 to influence cellular resistance to oxidative stress conditions and ferroptosis has profound implications. Research indicates that elevating GCH1 expression or supplementing with BH4 can protect various cell types against ferroptosis by diminishing lipid peroxidation and oxidative stress (185,190). Conversely, a lack or inhibition of GCH1 increases the vulnerability to this type of cell death (185,191).

Evidence linking ferroptosis and schizophrenia

Animal studies

Studies using animal models have provided compelling evidence linking alterations in iron metabolism to schizophrenia-associated behaviors. In one investigation, male Sprague-Dawley rats subjected to social isolation, an environmental stressor known to affect mental health, demonstrated notable iron level discrepancies in the brain. Specifically, isolated rats showed increased iron levels in the prefrontal cortex and decreased levels in the hippocampus compared with their group-housed counterparts. These iron imbalances were associated with behavioral changes characteristic of schizophrenia, including increased anxiety, altered locomotor activity and impaired cognitive functions, suggesting that the altered distribution of iron in these brain regions may contribute to the development of schizophrenia-associated symptoms (192).

Further research indicates that iron imbalances at different life stages can have profound effects. Rats experiencing iron deficiency during the perinatal period exhibited enduring neurochemical and behavioral abnormalities in adulthood, which persisted even after rectifying the iron deficiency through supplementation (193). This points to the lasting impact of early-life iron deficiency on brain function and its potential to contribute to psychiatric disorders. Additionally, experiments that induced iron overload in the hippocampus and prefrontal cortex of male rats led to the development of schizophrenia-associated behaviors (37), suggesting that both an excess and a deficiency of iron could foster changes in the brain associated with schizophrenia.

Another innovative study involved transferring gut microbiota from patients with schizophrenia into germ-free mice. This transfer caused the mice to exhibit schizophrenia-associated behaviors, such as decreased social interaction and hyperactivity (increased total distance traveled and higher average speed in the Open-field test). Furthermore, a bioinformatics analysis comparing transcriptional changes between the brains of mice that received schizophrenia-associated fecal microbiota and those given a control (phosphate-buffered saline) highlighted notable overlaps in differentially expressed genes associated with critical brain areas and pathways, including those involved in ferroptosis (194).

Ferroptosis-related genes

Advances in genomic research have shed light on the involvement of ferroptosis-related genes in schizophrenia. A recent study specifically explored the differential expression of ferroptosis-related genes in schizophrenia by employing bioinformatics analysis to compare patient and control groups. Key among the identified genes are TP53, VEGFA and PTGS2 (195), which have been highlighted as potential markers for ferroptosis within the context of schizophrenia. These genes are implicated in the regulation of oxidative stress responses and cell survival (196–198), and their altered expression in patients with schizophrenia indicates a potential disruption in cellular mechanisms that regulate oxidative stress and iron metabolism.

Building on these genetic insights, Lian et al (199) successfully developed a clinical diagnostic model based on ferroptosis-related hub genes, specifically DECR1, GJA1, EFN2L2, PSAT1, SLC7A11, SOX2 and YAP1. An effective clinical diagnostic model has been established based on these genes, enhancing the ability to diagnose and treat schizophrenia with a novel approach. Additionally, another study employing machine learning technology integrated various biological datasets to predict patterns of programmed cell death, including ferroptosis, in schizophrenia. This predictive model identified the ferroptosis-related genes ATG7 among the top 10 significant genes, underlining their importance in the progression of schizophrenia (200).

The impact of ancient viral elements on schizophrenia also presents a compelling avenue of research, particularly the role of the endogenous retrovirus group W member 1 (ERVW-1) retroviral element. This element has been shown to promote ferroptosis in neuronal cells by targeting and degrading key regulators, such as GPX4 and solute carrier family 3 member 2 (201). This contributes to increased iron levels and oxidative stress markers, decreased GSH levels and disrupted mitochondrial membrane potential, all of which are hallmarks of ferroptosis (202,203). Furthermore, the ERVW-1-induced effects could be reversed by the ferroptosis inhibitor ferrostatin-1 (201).

Iron dysregulation

In a case study of a patient initially diagnosed with Sydenham's chorea who later developed schizophrenia, autopsies revealed mineral accumulations, including predominantly iron, in the basal ganglia. These mineral deposits have been associated with disturbances in dopaminergic signaling, symptoms typical of schizophrenia and disorders characterized by irregular movements (204). In patients with schizophrenia, there was notably intense iron staining in the caudate nucleus compared with that in normal controls; however, it remains uncertain whether antipsychotic treatments induced this increase in iron staining (205). Further comprehensive autopsy analyses have indicated elevated iron concentrations in the prefrontal cortex, which is a critical area for cognitive processes, in patients with schizophrenia compared to matched controls (16.4 vs. 12.7 µmol/g). These iron levels were not associated with increased ferritin, which sequesters iron in a biologically inert form, thus suggesting the accumulation of potentially harmful free iron (37). Additionally, unlike in healthy individuals where iron accumulation increases with age, in patients with schizophrenia elevated iron levels were observed at a much younger age and remained stable across age, despite both groups having a similar age range at death (17–85 years for controls and 17–84 years for schizophrenia). And the difference in covariate-adjusted iron was substantial in the younger subcohort (age <35; 1.53 µmol/g) but marginal in the older subcohort (age ≥35 years; 0.46 µmol/g). This suggests that disruptions in iron regulation may be linked with developmental anomalies occurring early in the course of schizophrenia (37).

In the field of imaging studies, advanced techniques such as magnetic resonance spectroscopy and quantitative susceptibility mapping have provided a non-invasive method to examine the levels of brain iron in living patients with schizophrenia (206). Studies using these methods have shown that individuals with schizophrenia have distinct patterns of iron deposition. Particularly, increased iron levels have been documented in subcortical structures such as the thalamus and putamen, which are integral to dopaminergic pathways and are often implicated in schizophrenia (207,208). These imaging findings not only corroborate the autopsy studies regarding iron accumulation but also suggest that iron may modulate neurotransmitter systems directly involved in the symptomatology of schizophrenia (207).

Serological findings complement the neuropathological and imaging evidence of iron dysregulation in schizophrenia. Various studies have noted alterations in serum iron levels among patients with schizophrenia compared with healthy controls (209–211). Notably, lower serum log10ferritin:AST ratio levels and higher total serum iron have been observed in patients with schizophrenia (211), which may reflect an underlying imbalance in iron metabolism. These serological abnormalities are not isolated findings but are connected to broader physiological disruptions, including liver function, which is crucial in iron metabolism (209). Understanding these systemic changes is vital for developing targeted interventions that address the complex interplay between iron dysregulation and schizophrenia, potentially leading to more effective treatments for this disorder.

Therapeutic implications

N-acetylcysteine (NAC) supplementation

Decreased levels of antioxidant GSH in patients with schizophrenia have been well-documented and are considered a target for therapeutic intervention (212,213). NAC, as a precursor of GSH, plays a crucial role in attenuating oxidative stress and mitochondrial dysfunction (214), which are key contributors to the pathophysiology of schizophrenia. NAC has been shown to modulate neuroinflammatory pathways, protect against apoptosis and improve mitochondrial function (215). In GSH-deficient mouse models of schizophrenia, neurochemical changes were observed in the cortex, including elevated levels of glutamine, glutamate, N-acetylaspartate, myo-inositol, lactate, and alanine. NAC supplementation can effectively normalize these neurochemical changes during the development of the model mice, suggesting that NAC may play a therapeutic role in halting or mitigating the progression of schizophrenia (216).

Clinical trials have shown that NAC can markedly improve the symptoms of schizophrenia, particularly negative symptoms that are often less responsive to conventional antipsychotics (Table I) (217–226). For example, Berk et al (217) revealed notable improvements in negative symptoms as measured using the Positive and Negative Syndrome Scale in patients treated with NAC as an adjunct to their ongoing antipsychotic regimen. These clinical improvements were noted alongside enhancements in overall psychopathology scores, suggesting a broad therapeutic impact of NAC. In terms of cognitive improvements, NAC has been shown to exhibit a positive effect on cognitive functions in patients with schizophrenia. This includes enhancements in areas such as working memory and executive function (227). These cognitive improvements are vital, as they address core schizophrenia deficits that affect daily life and overall quality of life (228).

Table I.

Clinical trials of NAC supplementation in the treatment of schizophrenia.

Table I.

Clinical trials of NAC supplementation in the treatment of schizophrenia.

First author, yearGroupAge, yearsAverage duration of schizophrenia, yearsDaily dosage of NAC or placeboTreatment duration, weeksPositive symptomsNegative symptomsCognitive symptoms(Refs.)
Berk, 2008NAC (n=38); placebo (n=37)NAC, 44.6±11.2; placebo, 46.6±13.8Overall, 10.32.0 g24Not improvedImproved/(217)
Conus, 2018NAC (n=32); placebo (n=31)NAC, 26.1±6.1; placebo, 24.7±5.9NAC, 2.3; placebo, 2.12.7 g24Not improvedNot improvedImproved(218)
Rapado-Castro, 2017NAC (n=27); placebo (n=31)NAC, 38.6±12.2; placebo, 41.0±12.4NAC, 8.6; placebo, 11.12.0 g24//Improved(219)
Sepehrmanesh, 2018NAC (n=39); placebo (n=40)NAC, 38.7±1.9; placebo, 39.4±2.2NAC, 13.8; placebo, 17.01.2 g12ImprovedImprovedImproved(220)
Farokhnia, 2013NAC (n=21); placebo (n=21)NAC, 32.2±6.1; placebo, 33.4±7.0NAC, 6.9; placebo, 7.41.0 g during the first week, then 2.0 g8Not improvedImproved/(221)
Breier, 2018NAC (n=30); placebo (n=30)NAC, 22.2±4.2; placebo, 25.0±5.2NAC, 1.3; placebo, 1.4Started with 0.6 g and gradually increased to 3.6 g over the first 4 weeks52Not improvedImprovedNot improved(222)
Medvedev, 2021NAC (n=54); placebo (n=53) 18.0–65.0a12.22.0 g24ImprovedImproved/(223)
Rossell, 2016NAC (n=84); placebo (n=84) 18.0–65.0aNot provided2.0 g52Not improvedImprovedImproved(224)
Lavoie, 2008cCross-over design (n=11) 31.9±3.4b9.42.0 g8Not improvedNot improvedNot improved; MMN improved(225)
Carmeli, 2012cCross-over design (n=11)31.9±3.49.42.0 g8Not improvedNot improvedNot improved; MPS improved(226)

{ label (or @symbol) needed for fn[@id='tfn1-mmr-31-2-13402'] } Data are presented as the mean ± SD unless differently indicated. Data are presented as

a range and

b mean ± SEM. NAC, N-acetylcysteine; MMN, mismatch negativity; MPS, multivariate phase synchronization; /, not applicable.

c Based on the same clinical study.

The therapeutic potential of NAC supplements is not limited to mitigating oxidative stress. For instance, NAC has been shown to exhibit neuroprotective effects by reducing pro-inflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α, linked to schizophrenia. NAC also regulates glutamate levels through the cysteine-glutamate antiporter, influencing neurotransmitter pathways. These effects suggest that NAC may help prevent the progression of schizophrenia symptoms from prodromal stages to full-blown psychosis (229,230). Additionally, it may ameliorate side effects related to antipsychotic medications, such as akathisia and metabolic disturbances, thus improving patient adherence and overall quality of life (227,231). The safety and tolerability profile of NAC is also an advantage. It has been reported that NAC is generally well-tolerated by patients with minimal side effects. This aspect is crucial for long-term management strategies in schizophrenia, where treatments often continue for 1 to 5 years after the condition stabilizes (232).

Selenium supplementation

Given the role of oxidative stress in ferroptosis, treatments that reinforce the antioxidant defenses of the body, such as selenium, may help mitigate ferroptosis. Selenium, a vital trace element known for its antioxidant properties (233), has attracted interest in schizophrenia research due to the observed abnormalities in its levels among patients (234,235). Studies have shown that patients with schizophrenia typically have lower selenium concentrations in their bloodstream compared with healthy individuals (235,236). Additionally, a connection has been drawn between these depleted selenium levels and an increased risk of schizophrenia. Extensive epidemiological data from the European population have indicated an important association between lower selenium levels and increased schizophrenia prevalence (235). Selenium achieves its antioxidant effects primarily through selenoproteins, such as GPx and thioredoxin reductase, which reduce ROS and lipid hydroperoxides, thus protecting against oxidative stress. Moreover, these selenoproteins act as antioxidant enzymes that influence eicosanoid synthesis (lipid mediators involved in inflammatory responses), thereby affecting the balance between pro-inflammatory and anti-inflammatory eicosanoids and exerting an anti-inflammatory effect (237). This association highlights the role of selenium in combating oxidative stress and inflammation (238,239), factors that are believed to contribute to the onset and exacerbation of schizophrenia.

Clinical trials exploring the benefits of selenium supplementation for patients with schizophrenia have produced promising results. For example, it has been revealed that restoring selenium levels can lead to notable improvements in cognitive functions, such as memory, executive function and attention, which are frequently compromised in schizophrenia (240). Additionally, broader psychiatric improvements, including reductions in both positive and negative symptoms, have been observed, underscoring the wide-ranging benefits of correcting selenium deficiency (241). These outcomes suggest that selenium supplementation may be an effective adjunctive therapy in schizophrenia, capable of not only enhancing symptom management but also potentially addressing the underlying oxidative imbalances that contribute to disease progression.

PUFAs supplementation

While PUFAs are substrates for lipid peroxidation, their balanced intake can also modulate the composition and function of the cell membrane, affecting ferroptosis indirectly. Research into the effects of omega-3 fatty acids, particularly docosahexaenoic acid and eicosapentaenoic acid (EPA), reveals their potential to mitigate inflammatory processes and oxidative stress (242,243), which are pivotal in managing ferroptosis associated with schizophrenia.

Clinical studies and systematic reviews have indicated that supplementation with omega-3 fatty acids can ameliorate various psychopathological symptoms and metabolic disorders in patients with schizophrenia (244–247). For instance, a 12-week trial showed that omega-3 fatty acids supplementation significantly improved cognitive function and increased brain-derived neurotrophic factor (BDNF) levels, while reducing inflammatory markers such as IL-6, TNF-α and C-reactive protein (CRP) (244). Furthermore, omega-3 fatty acids have been reported to reduce the adverse effects of metabolic syndrome, conditions often exacerbated by antipsychotic medications, which typically promote weight gain and insulin resistance (244). Additionally, a review of 1,494 patients found significant improvements in general psychopathology and positive symptoms, particularly in severely ill patients receiving EPA at doses greater than 1 g/day, along with favorable effects on metabolic parameters such as serum triglycerides (247).

The incorporation of omega-3 fatty acids into cell membranes alters lipid profiles, changing the cellular vulnerability to lipid peroxidation that is central to ferroptosis (248,249). These fatty acids can decrease the production of pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α, while simultaneously enhancing the production of anti-inflammatory cytokines like IL-10 and IL-4 (250). The activation of inflammation can lead to ferroptosis (251), indicating that the anti-neuroinflammatory properties of omega-3 fatty acids may also contribute to reducing the levels of ferroptosis in neuronal cells (250,252,253). These capabilities suggest that omega-3 fatty acids could serve not only as supplementary treatments for symptom relief in schizophrenia but also as influential agents in modifying the fundamental mechanisms of the disease through the modulation of ferroptosis.

Iron chelation therapy

Iron chelation therapy offers a promising avenue for treating schizophrenia, given its efficacy in other neurological disorders, such as Parkinson's disease and Alzheimer's disease, where oxidative stress and iron dysregulation are implicated (254). Iron chelators, such as deferiprone, function by binding free iron in the body, thus mitigating the oxidative stress caused by excess iron (255). This is particularly important in the brain, where elevated iron levels can lead to the production of ROS, contributing to neuronal damage and neurodegeneration (256,257). Reducing iron-induced oxidative damage through chelation is an effective strategy in managing diseases such as Alzheimer's disease, Parkinson's disease and multiple sclerosis, where iron chelators have been shown to effectively lower iron levels in brain regions associated with these conditions, thereby potentially slowing disease progression and improving neurological outcomes (254,258,259).

In schizophrenia, similar mechanisms of iron-induced oxidative stress could play a role in the pathophysiology of the disorder. The accumulation of iron in the brain not only enhances oxidative stress but also promotes ferroptosis. In a study involving seven psychiatric patients with iron overload evidenced by abnormal serum ferritin, transferrin saturation, or excessive urinary iron, treatment with iron chelators led to significant clinical improvements (260). Iron chelation could, therefore, offer dual benefits in schizophrenia treatment by reducing both oxidative stress and ferroptosis. This therapeutic approach may be particularly relevant for patients exhibiting elevated ferritin levels or other indicators of disturbed iron metabolism. However, further research is needed to systematically assess the efficacy of iron chelation in schizophrenia and to validate this approach as a viable treatment option.

Conclusion

Exploring ferroptosis in the context of schizophrenia represents a promising frontier in psychiatric research, offering new perspectives on the cellular and molecular mechanisms underlying this complex disorder. The association between iron dysregulation, oxidative stress and lipid peroxidation central to ferroptosis suggests that this form of cell death could be integral to the pathophysiology of schizophrenia. Understanding the intricate balance of iron metabolism and the oxidative stress response within neural circuits could reveal novel therapeutic targets, potentially revolutionizing the management of schizophrenia. Future research should focus on the validation of ferroptosis markers in clinical settings and the development of targeted therapies that modulate iron homeostasis and antioxidant systems. By integrating the mechanisms of ferroptosis with existing knowledge of schizophrenia, researchers can pave the way for innovative treatments that not only alleviate symptoms but also address fundamental pathological processes, ultimately enhancing patient outcomes and quality of life.

Acknowledgements

Not applicable.

Funding

Funding: No funding was received.

Availability of data and materials

Not applicable.

Authors' contributions

SL contributed to the writing and editing of the present review. CL collected the information from the literature. Data authentication is not applicable. Both authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Solmi M, Seitidis G, Mavridis D, Correll CU, Dragioti E, Guimond S, Tuominen L, Dargél A, Carvalho AF, Fornaro M, et al: Incidence, prevalence, and global burden of schizophrenia-data, with critical appraisal, from the global burden of disease (GBD) 2019. Mol Psychiatry. 28:5319–5327. 2023. View Article : Google Scholar : PubMed/NCBI

2 

Schultz SH, North SW and Shields CG: Schizophrenia: A review. Am Fam Physician. 75:1821–1829. 2007.PubMed/NCBI

3 

Bassett AS, Collins EJ, Nuttall SE and Honer WG: Positive and negative symptoms in families with schizophrenia. Schizophr Res. 11:9–19. 1993. View Article : Google Scholar : PubMed/NCBI

4 

Azorin JM, Belzeaux R and Adida M: Negative symptoms in schizophrenia: where we have been and where we are heading. CNS Neurosci Ther. 20:801–808. 2014. View Article : Google Scholar : PubMed/NCBI

5 

Marder SR and Umbricht D: Negative symptoms in schizophrenia: Newly emerging measurements, pathways, and treatments. Schizophr Res. 258:71–77. 2023. View Article : Google Scholar : PubMed/NCBI

6 

McCutcheon RA, Keefe RSE and McGuire PK: Cognitive impairment in schizophrenia: Aetiology, pathophysiology, and treatment. Mol Psychiatry. 28:1902–1918. 2023. View Article : Google Scholar : PubMed/NCBI

7 

Bobes J, Arango C, Garcia-Garcia M and Rejas J; CLAMORS Study Collaborative Group, : Prevalence of negative symptoms in outpatients with schizophrenia spectrum disorders treated with antipsychotics in routine clinical practice: Findings from the CLAMORS study. J Clin Psychiatry. 71:280–286. 2010. View Article : Google Scholar : PubMed/NCBI

8 

Austin SF, Mors O, Budtz-Jørgensen E, Secher RG, Hjorthøj CR, Bertelsen M, Jeppesen P, Petersen L, Thorup A and Nordentoft M: Long-term trajectories of positive and negative symptoms in first episode psychosis: A 10 year follow-up study in the OPUS cohort. Schizophr Res. 168:84–91. 2015. View Article : Google Scholar : PubMed/NCBI

9 

Pandey A and Kalita KN: Treatment-resistant schizophrenia: How far have we traveled? Front Psychiatry. 13:9944252022. View Article : Google Scholar : PubMed/NCBI

10 

Ochoa S, Usall J, Cobo J, Labad X and Kulkarni J: Gender differences in schizophrenia and first-episode psychosis: A comprehensive literature review. Schizophr Res Treatment. 2012:9161982012. View Article : Google Scholar : PubMed/NCBI

11 

Andriopoulos I, Ellul J, Skokou M and Beratis S: Suicidality in the ‘prodromal’ phase of schizophrenia. Compr Psychiatry. 52:479–485. 2011. View Article : Google Scholar : PubMed/NCBI

12 

Donnelly L, Rathbone J and Adams CE: Haloperidol dose for the acute phase of schizophrenia. Cochrane Database Syst Rev. CD0019512013.PubMed/NCBI

13 

Charlson FJ, Ferrari AJ, Santomauro DF, Diminic S, Stockings E, Scott JG, McGrath JJ and Whiteford HA: Global epidemiology and burden of schizophrenia: Findings from the global burden of disease study 2016. Schizophr Bull. 44:1195–1203. 2018. View Article : Google Scholar : PubMed/NCBI

14 

Saito Y, Sakurai H, Kane JM, Schooler NR, Suzuki T, Mimura M and Uchida H: Predicting relapse with residual symptoms in schizophrenia: A secondary analysis of the PROACTIVE trial. Schizophr Res. 215:173–180. 2020. View Article : Google Scholar : PubMed/NCBI

15 

Patel KR, Cherian J, Gohil K and Atkinson D: Schizophrenia: Overview and treatment options. P T. 39:638–645. 2014.PubMed/NCBI

16 

Howes OD, Bukala BR and Beck K: Schizophrenia: From neurochemistry to circuits, symptoms and treatments. Nat Rev Neurol. 20:22–35. 2024. View Article : Google Scholar : PubMed/NCBI

17 

Butler AC, Chapman JE, Forman EM and Beck AT: The empirical status of cognitive-behavioral therapy: A review of meta-analyses. Clin Psychol Rev. 26:17–31. 2006. View Article : Google Scholar : PubMed/NCBI

18 

Kim SH and Park S: Effectiveness of family interventions for patients with schizophrenia: A systematic review and meta-analysis. Int J Ment Health Nurs. 32:1598–1615. 2023. View Article : Google Scholar : PubMed/NCBI

19 

Sinclair DJM, Zhao S, Qi F, Nyakyoma K, Kwong JSW and Adams CE: Electroconvulsive therapy for treatment-resistant schizophrenia. Schizophr Bull. 45:730–732. 2019. View Article : Google Scholar : PubMed/NCBI

20 

Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, et al: Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell. 149:1060–1072. 2012. View Article : Google Scholar : PubMed/NCBI

21 

Yang WS and Stockwell BR: Ferroptosis: Death by lipid peroxidation. Trends Cell Biol. 26:165–176. 2016. View Article : Google Scholar : PubMed/NCBI

22 

Liu Y, Wan Y, Jiang Y, Zhang L and Cheng W: GPX4: The hub of lipid oxidation, ferroptosis, disease and treatment. Biochim Biophys Acta Rev Cancer. 1878:1888902023. View Article : Google Scholar : PubMed/NCBI

23 

Zhang XD, Liu ZY, Wang MS, Guo YX, Wang XK, Luo K, Huang S and Li RF: Mechanisms and regulations of ferroptosis. Front Immunol. 14:12694512023. View Article : Google Scholar : PubMed/NCBI

24 

Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, Roberts MA, Tong B, Maimone TJ, Zoncu R, et al: The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 575:688–692. 2019. View Article : Google Scholar : PubMed/NCBI

25 

Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold I, Goya Grocin A, Xavier da Silva TN, Panzilius E, Scheel CH, et al: FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 575:693–698. 2019. View Article : Google Scholar : PubMed/NCBI

26 

Chen X, Comish PB, Tang D and Kang R: Characteristics and biomarkers of ferroptosis. Front Cell Dev Biol. 9:6371622021. View Article : Google Scholar : PubMed/NCBI

27 

Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, 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. 16:1180–1191. 2014. View Article : Google Scholar : PubMed/NCBI

28 

Yagoda N, von Rechenberg M, Zaganjor E, Bauer AJ, Yang WS, Fridman DJ, Wolpaw AJ, Smukste I, Peltier JM, Boniface JJ, et al: RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature. 447:864–868. 2007. View Article : Google Scholar : PubMed/NCBI

29 

Riegman M, Sagie L, Galed C, Levin T, Steinberg N, Dixon SJ, Wiesner U, Bradbury MS, Niethammer P, Zaritsky A and Overholtzer M: Ferroptosis occurs through an osmotic mechanism and propagates independently of cell rupture. Nat Cell Biol. 22:1042–1048. 2020. View Article : Google Scholar : PubMed/NCBI

30 

Demuynck R, Efimova I, Naessens F and Krysko DV: Immunogenic ferroptosis and where to find it? J Immunother Cancer. 9:e0034302021. View Article : Google Scholar : PubMed/NCBI

31 

Jiang X, Stockwell BR and Conrad M: Ferroptosis: Mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 22:266–282. 2021. View Article : Google Scholar : PubMed/NCBI

32 

Liang D, Minikes AM and Jiang X: Ferroptosis at the intersection of lipid metabolism and cellular signaling. Mol Cell. 82:2215–2227. 2022. View Article : Google Scholar : PubMed/NCBI

33 

Tang D, Chen X, Kang R and Kroemer G: Ferroptosis: Molecular mechanisms and health implications. Cell Res. 31:107–125. 2021. View Article : Google Scholar : PubMed/NCBI

34 

Chen X, Kang R, Kroemer G and Tang D: Broadening horizons: The role of ferroptosis in cancer. Nat Rev Clin Oncol. 18:280–296. 2021. View Article : Google Scholar : PubMed/NCBI

35 

Wang Y, Wu S, Li Q, Sun H and Wang H: Pharmacological inhibition of ferroptosis as a therapeutic target for neurodegenerative diseases and strokes. Adv Sci (Weinh). 10:e23003252023. View Article : Google Scholar : PubMed/NCBI

36 

Bitanihirwe BKY and Woo TUW: Oxidative stress in schizophrenia: An integrated approach. Neurosci Biobehav Rev. 35:878–893. 2011. View Article : Google Scholar : PubMed/NCBI

37 

Lotan A, Luza S, Opazo CM, Ayton S, Lane DJR, Mancuso S, Pereira A, Sundram S, Weickert CS, Bousman C, et al: Perturbed iron biology in the prefrontal cortex of people with schizophrenia. Mol Psychiatry. 28:2058–2070. 2023. View Article : Google Scholar : PubMed/NCBI

38 

Götz ME, Künig G, Riederer P and Youdim MB: Oxidative stress: Free radical production in neural degeneration. Pharmacol Ther. 63:37–122. 1994. View Article : Google Scholar : PubMed/NCBI

39 

David S, Jhelum P, Ryan F, Jeong SY and Kroner A: Dysregulation of iron homeostasis in the central nervous system and the role of ferroptosis in neurodegenerative disorders. Antioxid Redox Signal. 37:150–170. 2022. View Article : Google Scholar : PubMed/NCBI

40 

Qin Y, He Y, She Q, Larese-Casanova P, Li P and Chai Y: Heterogeneity in respiratory electron transfer and adaptive iron utilization in a bacterial biofilm. Nat Commun. 10:37022019. View Article : Google Scholar : PubMed/NCBI

41 

Gomme PT, McCann KB and Bertolini J: Transferrin: Structure, function and potential therapeutic actions. Drug Discov Today. 10:267–273. 2005. View Article : Google Scholar : PubMed/NCBI

42 

Kakhlon O and Cabantchik ZI: The labile iron pool: Characterization, measurement, and participation in cellular processes(1). Free Radic Biol Med. 33:1037–1046. 2002. View Article : Google Scholar : PubMed/NCBI

43 

Worwood M: Ferritin. Blood Rev. 4:259–269. 1990. View Article : Google Scholar : PubMed/NCBI

44 

MacKenzie EL, Iwasaki K and Tsuji Y: Intracellular iron transport and storage: From molecular mechanisms to health implications. Antioxid Redox Signal. 10:997–1030. 2008. View Article : Google Scholar : PubMed/NCBI

45 

Reinert A, Morawski M, Seeger J, Arendt T and Reinert T: Iron concentrations in neurons and glial cells with estimates on ferritin concentrations. BMC Neurosci. 20:252019. View Article : Google Scholar : PubMed/NCBI

46 

Sunkara S, Radulović S, Lipovšek S, Birkl C, Eggenreich S, Birkl-Toeglhofer AM, Schinagl M, Funk D, Stöger-Pollach M, Haybaeck J, et al: Autolysis affects the iron cargo of ferritins in neurons and glial cells at different rates in the human brain. Cell Mol Neurobiol. 43:2909–2923. 2023. View Article : Google Scholar : PubMed/NCBI

47 

Hansen TM, Nielsen H, Bernth N and Moos T: Expression of ferritin protein and subunit mRNAs in normal and iron deficient rat brain. Brain Res Mol Brain Res. 65:186–197. 1999. View Article : Google Scholar : PubMed/NCBI

48 

Wang P, Ren Q, Shi M, Liu Y, Bai H and Chang YZ: Overexpression of mitochondrial ferritin enhances blood-brain barrier integrity following ischemic stroke in mice by maintaining iron homeostasis in endothelial cells. Antioxidants (Basel). 11:12572022. View Article : Google Scholar : PubMed/NCBI

49 

Wu H, Liu Q, Shan X, Gao W and Chen Q: ATM orchestrates ferritinophagy and ferroptosis by phosphorylating NCOA4. Autophagy. 19:2062–2077. 2023. View Article : Google Scholar : PubMed/NCBI

50 

Zhang DL and Rouault TA: How does hepcidin hinder ferroportin activity? Blood. 131:840–842. 2018. View Article : Google Scholar : PubMed/NCBI

51 

Fang X, Ardehali H, Min J and Wang F: The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease. Nat Rev Cardiol. 20:7–23. 2023. View Article : Google Scholar : PubMed/NCBI

52 

Delaby C, Pilard N, Gonçalves AS, Beaumont C and Canonne-Hergaux F: Presence of the iron exporter ferroportin at the plasma membrane of macrophages is enhanced by iron loading and down-regulated by hepcidin. Blood. 106:3979–3984. 2005. View Article : Google Scholar : PubMed/NCBI

53 

Ganz T: Hepcidin and its role in regulating systemic iron metabolism. Hematology Am Soc Hematol Educ Program. 2006:29–35. 2006. View Article : Google Scholar : PubMed/NCBI

54 

Ramey G, Deschemin JC, Durel B, Canonne-Hergaux F, Nicolas G and Vaulont S: Hepcidin targets ferroportin for degradation in hepatocytes. Haematologica. 95:501–504. 2010. View Article : Google Scholar : PubMed/NCBI

55 

Qiu B, Zandkarimi F, Bezjian CT, Reznik E, Soni RK, Gu W, Jiang X and Stockwell BR: Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis. Cell. 187:1177–1190.e18. 2024. View Article : Google Scholar : PubMed/NCBI

56 

Yang WS, Kim KJ, Gaschler MM, Patel M, Shchepinov MS and Stockwell BR: Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci USA. 113:E4966–E4975. 2016. View Article : Google Scholar : PubMed/NCBI

57 

Talvenmäki H, Lallukka N, Survo S and Romantschuk M: Fenton's reaction-based chemical oxidation in suboptimal conditions can lead to mobilization of oil hydrocarbons but also contribute to the total removal of volatile compounds. Environ Sci Pollut Res Int. 26:34670–34684. 2019. View Article : Google Scholar : PubMed/NCBI

58 

Henning Y, Blind US, Larafa S, Matschke J and Fandrey J: Hypoxia aggravates ferroptosis in RPE cells by promoting the Fenton reaction. Cell Death Dis. 13:6622022. View Article : Google Scholar : PubMed/NCBI

59 

Abe C and Miyazawa T and Miyazawa T: Current use of Fenton reaction in drugs and food. Molecules. 27:54512022. View Article : Google Scholar : PubMed/NCBI

60 

Valgimigli L: Lipid peroxidation and antioxidant protection. Biomolecules. 13:12912023. View Article : Google Scholar : PubMed/NCBI

61 

Minotti G and Aust SD: The role of iron in oxygen radical mediated lipid peroxidation. Chem Biol Interact. 71:1–19. 1989. View Article : Google Scholar : PubMed/NCBI

62 

Gaschler MM and Stockwell BR: Lipid peroxidation in cell death. Biochem Biophys Res Commun. 482:419–425. 2017. View Article : Google Scholar : PubMed/NCBI

63 

Janero DR: Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free Radic Biol Med. 9:515–540. 1990. View Article : Google Scholar : PubMed/NCBI

64 

Mas-Bargues C, Escrivá C, Dromant M, Borrás C and Viña J: Lipid peroxidation as measured by chromatographic determination of malondialdehyde. Human plasma reference values in health and disease. Arch Biochem Biophys. 709:1089412021. View Article : Google Scholar : PubMed/NCBI

65 

Li Y, Zhao T, Li J, Xia M, Li Y, Wang X, Liu C, Zheng T, Chen R, Kan D, et al: Oxidative stress and 4-hydroxy-2-nonenal (4-HNE): Implications in the pathogenesis and treatment of aging-related diseases. J Immunol Res. 2022:22339062022.PubMed/NCBI

66 

Dalleau S, Baradat M, Guéraud F and Huc L: Cell death and diseases related to oxidative stress: 4-Hydroxynonenal (HNE) in the balance. Cell Death Differ. 20:1615–1630. 2013. View Article : Google Scholar : PubMed/NCBI

67 

Zhang X, Hou L, Guo Z, Wang G, Xu J, Zheng Z, Sun K and Guo F: Lipid peroxidation in osteoarthritis: Focusing on 4-hydroxynonenal, malondialdehyde, and ferroptosis. Cell Death Discov. 9:3202023. View Article : Google Scholar : PubMed/NCBI

68 

Butterfield DA: Brain lipid peroxidation and alzheimer disease: Synergy between the Butterfield and Mattson laboratories. Ageing Res Rev. 64:1010492020. View Article : Google Scholar : PubMed/NCBI

69 

Villalón-García I, Povea-Cabello S, Álvarez-Córdoba M, Talaverón-Rey M, Suárez-Rivero JM, Suárez-Carrillo A, Munuera-Cabeza M, Reche-López D, Cilleros-Holgado P, Piñero-Pérez R and Sánchez-Alcázar JA: Vicious cycle of lipid peroxidation and iron accumulation in neurodegeneration. Neural Regen Res. 18:1196–1202. 2023. View Article : Google Scholar : PubMed/NCBI

70 

Shichiri M: The role of lipid peroxidation in neurological disorders. J Clin Biochem Nutr. 54:151–160. 2014. View Article : Google Scholar : PubMed/NCBI

71 

Dietrich-Muszalska A and Kontek B: Lipid peroxidation in patients with schizophrenia. Psychiatry Clin Neurosci. 64:469–475. 2010. View Article : Google Scholar : PubMed/NCBI

72 

Bošković M, Vovk T, Kores Plesničar B and Grabnar I: Oxidative stress in schizophrenia. Curr Neuropharmacol. 9:301–312. 2011. View Article : Google Scholar : PubMed/NCBI

73 

Chen P, Wang D, Xiu M, Chen D, Lackey B, Wu HE, Wang L and Zhang X: Association of transferrin gene polymorphism with cognitive deficits and psychiatric symptoms in patients with chronic schizophrenia. J Clin Med. 11:64142022. View Article : Google Scholar : PubMed/NCBI

74 

Yeh S and Chang C: Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells. Proc Natl Acad Sci USA. 93:5517–5521. 1996. View Article : Google Scholar : PubMed/NCBI

75 

Moore JMR, Galicia SJ, McReynolds AC, Nguyen NH, Scanlan TS and Guy RK: Quantitative proteomics of the thyroid hormone receptor-coregulator interactions. J Biol Chem. 279:27584–27590. 2004. View Article : Google Scholar : PubMed/NCBI

76 

Kollara A and Brown TJ: Expression and function of nuclear receptor co-activator 4: Evidence of a potential role independent of co-activator activity. Cell Mol Life Sci. 69:3895–3909. 2012. View Article : Google Scholar : PubMed/NCBI

77 

Heinlein CA, Ting HJ, Yeh S and Chang C: Identification of ARA70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor gamma. J Biol Chem. 274:16147–16152. 1999. View Article : Google Scholar : PubMed/NCBI

78 

Zhou ZX, He B, Hall SH, Wilson EM and French FS: Domain interactions between coregulator ARA(70) and the androgen receptor (AR). Mol Endocrinol. 16:287–300. 2002. View Article : Google Scholar : PubMed/NCBI

79 

Mancias JD, Pontano Vaites L, Nissim S, Biancur DE, Kim AJ, Wang X, Liu Y, Goessling W, Kimmelman AC and Harper JW: Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis. Elife. 4:e103082015. View Article : Google Scholar : PubMed/NCBI

80 

Federico G, Carrillo F, Dapporto F, Chiariello M, Santoro M, Bellelli R and Carlomagno F: NCOA4 links iron bioavailability to DNA metabolism. Cell Rep. 40:1112072022. View Article : Google Scholar : PubMed/NCBI

81 

Kuno S, Fujita H, Tanaka YK, Ogra Y and Iwai K: Iron-induced NCOA4 condensation regulates ferritin fate and iron homeostasis. EMBO Rep. 23:e542782022. View Article : Google Scholar : PubMed/NCBI

82 

Bellelli R, Federico G, Matte' A, Colecchia D, Iolascon A, Chiariello M, Santoro M, De Franceschi L and Carlomagno F: NCOA4 deficiency impairs systemic iron homeostasis. Cell Rep. 14:411–421. 2016. View Article : Google Scholar : PubMed/NCBI

83 

Arcos M, Liu Z, Villareal LB, Velez PK, Desai SP, Noureddine A, Zheng H, Martin DR, Brinker J, Zhang D and Xue X: Myeloid NCOA4 sequesters KEAP1 to reduce ferroptosis for protection against salmonellosis in mice. Res Sq [Preprint]. rs.3.rs-4278310. 2024.PubMed/NCBI

84 

Mancias JD, Wang X, Gygi SP, Harper JW and Kimmelman AC: Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature. 509:105–109. 2014. View Article : Google Scholar : PubMed/NCBI

85 

Kuno S and Iwai K: Oxygen modulates iron homeostasis by switching iron sensing of NCOA4. J Biol Chem. 299:1047012023. View Article : Google Scholar : PubMed/NCBI

86 

Gryzik M, Srivastava A, Longhi G, Bertuzzi M, Gianoncelli A, Carmona F, Poli M and Arosio P: Expression and characterization of the ferritin binding domain of nuclear receptor coactivator-4 (NCOA4). Biochim Biophys Acta Gen Subj. 1861:2710–2716. 2017. View Article : Google Scholar : PubMed/NCBI

87 

Zhao H, Lu Y, Zhang J, Sun Z, Cheng C, Liu Y, Wu L, Zhang M, He W, Hao S and Li K: NCOA4 requires a [3Fe-4S] to sense and maintain the iron homeostasis. J Biol Chem. 300:1056122024. View Article : Google Scholar : PubMed/NCBI

88 

Li HY, Wei TT, Zhuang M, Tan CY, Xie TH, Cai J, Yao Y and Zhu L: Iron derived from NCOA4-mediated ferritinophagy causes cellular senescence via the cGAS-STING pathway. Cell Death Discov. 9:4192023. View Article : Google Scholar : PubMed/NCBI

89 

Hoelzgen F, Nguyen TTP, Klukin E, Boumaiza M, Srivastava AK, Kim EY, Zalk R, Shahar A, Cohen-Schwartz S, Meyron-Holtz EG, et al: Structural basis for the intracellular regulation of ferritin degradation. Nat Commun. 15:38022024. View Article : Google Scholar : PubMed/NCBI

90 

Yuan L, Sun Y, Zhou N, Wu W, Zheng W and Wang Y: Dihydroquercetin attenuates silica-induced pulmonary fibrosis by inhibiting ferroptosis signaling pathway. Front Pharmacol. 13:8456002022. View Article : Google Scholar : PubMed/NCBI

91 

Lahiri V, Hawkins WD and Klionsky DJ: Watch what you (self-) eat: Autophagic mechanisms that modulate metabolism. Cell Metab. 29:803–826. 2019. View Article : Google Scholar : PubMed/NCBI

92 

Vermot A, Petit-Härtlein I, Smith SME and Fieschi F: NADPH oxidases (NOX): An overview from discovery, molecular mechanisms to physiology and pathology. Antioxidants (Basel). 10:8902021. View Article : Google Scholar : PubMed/NCBI

93 

Nazari B, Jaquet V and Krause KH: NOX family NADPH oxidases in mammals: Evolutionary conservation and isoform-defining sequences. Redox Biol. 66:1028512023. View Article : Google Scholar : PubMed/NCBI

94 

Lambeth JD: Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy. Free Radic Biol Med. 43:332–347. 2007. View Article : Google Scholar : PubMed/NCBI

95 

Chen F, Haigh S, Barman S and Fulton DJR: From form to function: The role of Nox4 in the cardiovascular system. Front Physiol. 3:4122012. View Article : Google Scholar : PubMed/NCBI

96 

Altenhöfer S, Radermacher KA, Kleikers PWM, Wingler K and Schmidt HHHW: Evolution of NADPH oxidase inhibitors: Selectivity and mechanisms for target engagement. Antioxid Redox Signal. 23:406–427. 2015. View Article : Google Scholar : PubMed/NCBI

97 

Martyn KD, Frederick LM, von Loehneysen K, Dinauer MC and Knaus UG: Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases. Cell Signal. 18:69–82. 2006. View Article : Google Scholar : PubMed/NCBI

98 

Nisimoto Y, Diebold BA, Cosentino-Gomes D and Lambeth JD: Nox4: A hydrogen peroxide-generating oxygen sensor. Biochemistry. 53:5111–5120. 2014. View Article : Google Scholar : PubMed/NCBI

99 

Serrander L, Cartier L, Bedard K, Banfi B, Lardy B, Plastre O, Sienkiewicz A, Fórró L, Schlegel W and Krause KH: NOX4 activity is determined by mRNA levels and reveals a unique pattern of ROS generation. Biochem J. 406:105–114. 2007. View Article : Google Scholar : PubMed/NCBI

100 

Di Marzo N, Chisci E and Giovannoni R: The role of hydrogen peroxide in redox-dependent signaling: Homeostatic and pathological responses in mammalian cells. Cells. 7:1562018. View Article : Google Scholar : PubMed/NCBI

101 

Feng S, Tang D, Wang Y, Li X, Bao H, Tang C, Dong X, Li X, Yang Q, Yan Y, et al: The mechanism of ferroptosis and its related diseases. Mol Biomed. 4:332023. View Article : Google Scholar : PubMed/NCBI

102 

Rada B and Leto TL: Oxidative innate immune defenses by Nox/Duox family NADPH oxidases. Contrib Microbiol. 15:164–187. 2008. View Article : Google Scholar : PubMed/NCBI

103 

Konno T, Melo EP, Chambers JE and Avezov E: Intracellular sources of ROS/H2O2 in health and neurodegeneration: Spotlight on endoplasmic reticulum. Cells. 10:2332021. View Article : Google Scholar : PubMed/NCBI

104 

Yin H, Xu L and Porter NA: Free radical lipid peroxidation: Mechanisms and analysis. Chem Rev. 111:5944–5972. 2011. View Article : Google Scholar : PubMed/NCBI

105 

Rochette L, Dogon G, Rigal E, Zeller M, Cottin Y and Vergely C: Lipid peroxidation and iron metabolism: Two corner stones in the homeostasis control of ferroptosis. Int J Mol Sci. 24:4492022. View Article : Google Scholar : PubMed/NCBI

106 

Zhang H, Wang A, Li G, Zhai Q, Huang Z, Wang X, Cao Z, Liu L, Liu G, Chen B, et al: Osteoporotic bone loss from excess iron accumulation is driven by NOX4-triggered ferroptosis in osteoblasts. Free Radic Biol Med. 198:123–136. 2023. View Article : Google Scholar : PubMed/NCBI

107 

Mancardi D, Mezzanotte M, Arrigo E, Barinotti A and Roetto A: Iron overload, oxidative stress, and ferroptosis in the failing heart and liver. Antioxidants (Basel). 10:18642021. View Article : Google Scholar : PubMed/NCBI

108 

Orino K, Lehman L, Tsuji Y, Ayaki H, Torti SV and Torti FM: Ferritin and the response to oxidative stress. Biochem J. 357:241–247. 2001. View Article : Google Scholar : PubMed/NCBI

109 

Zhu J, Xiong Y, Zhang Y, Wen J, Cai N, Cheng K, Liang H and Zhang W: The Molecular mechanisms of regulating oxidative stress-induced ferroptosis and therapeutic strategy in tumors. Oxid Med Cell Longev. 2020:88107852020. View Article : Google Scholar : PubMed/NCBI

110 

Cipriano A, Viviano M, Feoli A, Milite C, Sarno G, Castellano S and Sbardella G: NADPH oxidases: From molecular mechanisms to current inhibitors. J Med Chem. 66:11632–11655. 2023. View Article : Google Scholar : PubMed/NCBI

111 

Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, et al: Regulation of ferroptotic cancer cell death by GPX4. Cell. 156:317–331. 2014. View Article : Google Scholar : PubMed/NCBI

112 

Wu J, Feng Z, Chen L, Li Y, Bian H, Geng J, Zheng ZH, Fu X, Pei Z, Qin Y, et al: TNF antagonist sensitizes synovial fibroblasts to ferroptotic cell death in collagen-induced arthritis mouse models. Nat Commun. 13:6762022. View Article : Google Scholar : PubMed/NCBI

113 

Wang L, Liu Y, Du T, Yang H, Lei L, Guo M, Ding HF, Zhang J, Wang H, Chen X and Yan C: ATF3 promotes erastin-induced ferroptosis by suppressing system Xc. Cell Death Differ. 27:662–675. 2020. View Article : Google Scholar : PubMed/NCBI

114 

Inaba Y, Hashiuchi E, Watanabe H, Kimura K, Oshima Y, Tsuchiya K, Murai S, Takahashi C, Matsumoto M, Kitajima S, et al: The transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice. Nat Commun. 14:1672023. View Article : Google Scholar : PubMed/NCBI

115 

Liu S, Li Z, Lan S, Hao H, Baz AA, Yan X, Gao P, Chen S and Chu Y: The dual roles of activating transcription factor 3 (ATF3) in inflammation, apoptosis, ferroptosis, and pathogen infection responses. Int J Mol Sci. 25:8242024. View Article : Google Scholar : PubMed/NCBI

116 

Wu J, Huang Y, Zhou X, Xiang Z, Yang Z, Meng D, Wu D, Zhang J and Yang J: ATF3 and its emerging role in atherosclerosis: A narrative review. Cardiovasc Diagn Ther. 12:926–942. 2022. View Article : Google Scholar : PubMed/NCBI

117 

Shao CJ, Zhou HL, Gao XZ and Xu CF: Downregulation of miR-221-3p promotes the ferroptosis in gastric cancer cells via upregulation of ATF3 to mediate the transcription inhibition of GPX4 and HRD1. Transl Oncol. 32:1016492023. View Article : Google Scholar : PubMed/NCBI

118 

Feng Z, Cao K, Sun H and Liu X: SEH1L siliencing induces ferroptosis and suppresses hepatocellular carcinoma progression via ATF3/HMOX1/GPX4 axis. Apoptosis. 29:1723–1737. 2024. View Article : Google Scholar : PubMed/NCBI

119 

Lu H, Zheng Y and Wang D: ATF3 affects osteogenic differentiation in inflammatory hPDLSCs by mediating ferroptosis via regulating the Nrf2/HO-1 signaling pathway. Tissue Cell. 89:1024472024. View Article : Google Scholar : PubMed/NCBI

120 

Lei P, Bai T and Sun Y: Mechanisms of ferroptosis and relations with regulated cell death: A review. Front Physiol. 10:1392019. View Article : Google Scholar : PubMed/NCBI

121 

Wu Y, Zhang S, Gong X, Tam S, Xiao D, Liu S and Tao Y: The epigenetic regulators and metabolic changes in ferroptosis-associated cancer progression. Mol Cancer. 19:392020. View Article : Google Scholar : PubMed/NCBI

122 

Wei S, Wang H, Lu C, Malmut S, Zhang J, Ren S, Yu G, Wang W, Tang DD and Yan C: The activating transcription factor 3 protein suppresses the oncogenic function of mutant p53 proteins. J Biol Chem. 289:8947–8959. 2014. View Article : Google Scholar : PubMed/NCBI

123 

Li X, Guo M, Cai L, Du T, Liu Y, Ding HF, Wang H, Zhang J, Chen X and Yan C: Competitive ubiquitination activates the tumor suppressor p53. Cell Death Differ. 27:1807–1818. 2020. View Article : Google Scholar : PubMed/NCBI

124 

Zhao J, Li X, Guo M, Yu J and Yan C: The common stress responsive transcription factor ATF3 binds genomic sites enriched with p300 and H3K27ac for transcriptional regulation. BMC Genomics. 17:3352016. View Article : Google Scholar : PubMed/NCBI

125 

Akbarpour Arsanjani A, Abuei H, Behzad-Behbahani A, Bagheri Z, Arabsolghar R and Farhadi A: Activating transcription factor 3 inhibits NF-κB p65 signaling pathway and mediates apoptosis and cell cycle arrest in cervical cancer cells. Infect Agent Cancer. 17:622022. View Article : Google Scholar : PubMed/NCBI

126 

Kwon JW, Kwon HK, Shin HJ, Choi YM, Anwar MA and Choi S: Activating transcription factor 3 represses inflammatory responses by binding to the p65 subunit of NF-κB. Sci Rep. 5:144702015. View Article : Google Scholar : PubMed/NCBI

127 

Liu J, Zhang C, Wang J, Hu W and Feng Z: The regulation of ferroptosis by tumor suppressor p53 and its pathway. Int J Mol Sci. 21:83872020. View Article : Google Scholar : PubMed/NCBI

128 

Kang R, Kroemer G and Tang D: The tumor suppressor protein p53 and the ferroptosis network. Free Radic Biol Med. 133:162–168. 2019. View Article : Google Scholar : PubMed/NCBI

129 

Jiang L, Kon N, Li T, Wang SJ, Su T, Hibshoosh H, Baer R and Gu W: Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 520:57–62. 2015. View Article : Google Scholar : PubMed/NCBI

130 

Comporti M: Glutathione depleting agents and lipid peroxidation. Chem Phys Lipids. 45:143–169. 1987. View Article : Google Scholar : PubMed/NCBI

131 

Ou Y, Wang SJ, Li D, Chu B and Gu W: Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses. Proc Natl Acad Sci USA. 113:E6806–E6812. 2016. View Article : Google Scholar : PubMed/NCBI

132 

Suzuki S, Tanaka T, Poyurovsky MV, Nagano H, Mayama T, Ohkubo S, Lokshin M, Hosokawa H, Nakayama T, Suzuki Y, et al: Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc Natl Acad Sci USA. 107:7461–7466. 2010. View Article : Google Scholar : PubMed/NCBI

133 

Hu W, Zhang C, Wu R, Sun Y, Levine A and Feng Z: Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc Natl Acad Sci USA. 107:7455–7460. 2010. View Article : Google Scholar : PubMed/NCBI

134 

Engeland K: Cell cycle regulation: p53-p21-RB signaling. Cell Death Differ. 29:946–960. 2022. View Article : Google Scholar : PubMed/NCBI

135 

Engeland K: Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM. Cell Death Differ. 25:114–132. 2018. View Article : Google Scholar : PubMed/NCBI

136 

Chen W, Sun Z, Wang XJ, Jiang T, Huang Z, Fang D and Zhang DD: Direct interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response. Mol Cell. 34:663–673. 2009. View Article : Google Scholar : PubMed/NCBI

137 

Pouremamali F, Pouremamali A, Dadashpour M, Soozangar N and Jeddi F: An update of Nrf2 activators and inhibitors in cancer prevention/promotion. Cell Commun Signal. 20:1002022. View Article : Google Scholar : PubMed/NCBI

138 

Villeneuve NF, Sun Z, Chen W and Zhang DD: Nrf2 and p21 regulate the fine balance between life and death by controlling ROS levels. Cell Cycle. 8:3255–3256. 2009. View Article : Google Scholar : PubMed/NCBI

139 

Franklin CC, Backos DS, Mohar I, White CC, Forman HJ and Kavanagh TJ: Structure, function, and post-translational regulation of the catalytic and modifier subunits of glutamate cysteine ligase. Mol Aspects Med. 30:86–98. 2009. View Article : Google Scholar : PubMed/NCBI

140 

Lu SC: Regulation of glutathione synthesis. Mol Aspects Med. 30:42–59. 2009. View Article : Google Scholar : PubMed/NCBI

141 

Dahl EL and Mulcahy RT: Cell-type specific differences in glutamate cysteine ligase transcriptional regulation demonstrate independent subunit control. Toxicol Sci. 61:265–272. 2001. View Article : Google Scholar : PubMed/NCBI

142 

Wang X, Shen T, Lian J, Deng K, Qu C, Li E, Li G, Ren Y, Wang Z, Jiang Z, et al: Resveratrol reduces ROS-induced ferroptosis by activating SIRT3 and compensating the GSH/GPX4 pathway. Mol Med. 29:1372023. View Article : Google Scholar : PubMed/NCBI

143 

Weaver K and Skouta R: The selenoprotein glutathione peroxidase 4: From molecular mechanisms to novel therapeutic opportunities. Biomedicines. 10:8912022. View Article : Google Scholar : PubMed/NCBI

144 

Xie Y, Kang R, Klionsky DJ and Tang D: GPX4 in cell death, autophagy, and disease. Autophagy. 19:2621–2638. 2023. View Article : Google Scholar : PubMed/NCBI

145 

Labrecque CL and Fuglestad B: Electrostatic drivers of GPx4 interactions with membrane, lipids, and DNA. Biochemistry. 60:2761–2772. 2021. View Article : Google Scholar : PubMed/NCBI

146 

Yan HF, Zou T, Tuo QZ, Xu S, Li H, Belaidi AA and Lei P: Ferroptosis: Mechanisms and links with diseases. Signal Transduct Target Ther. 6:492021. View Article : Google Scholar : PubMed/NCBI

147 

Sugezawa K, Morimoto M, Yamamoto M, Matsumi Y, Nakayama Y, Hara K, Uejima C, Kihara K, Matsunaga T, Tokuyasu N, et al: GPX4 regulates tumor cell proliferation via suppressing ferroptosis and exhibits prognostic significance in gastric cancer. Anticancer Res. 42:5719–5729. 2022. View Article : Google Scholar : PubMed/NCBI

148 

Li J, Liu J, Zhou Z, Wu R, Chen X, Yu C, Stockwell B, Kroemer G, Kang R and Tang D: Tumor-specific GPX4 degradation enhances ferroptosis-initiated antitumor immune response in mouse models of pancreatic cancer. Sci Transl Med. 15:eadg30492023. View Article : Google Scholar : PubMed/NCBI

149 

Li H, Sun Y, Yao Y, Ke S, Zhang N, Xiong W, Shi J, He C, Xiao X, Yu H, et al: USP8-governed GPX4 homeostasis orchestrates ferroptosis and cancer immunotherapy. Proc Natl Acad Sci USA. 121:e23155411212024. View Article : Google Scholar : PubMed/NCBI

150 

Shimizu J, Murao A, Nofi C, Wang P and Aziz M: Extracellular CIRP promotes GPX4-mediated ferroptosis in sepsis. Front Immunol. 13:9038592022. View Article : Google Scholar : PubMed/NCBI

151 

Niu B, Liao K, Zhou Y, Wen T, Quan G, Pan X and Wu C: Application of glutathione depletion in cancer therapy: Enhanced ROS-based therapy, ferroptosis, and chemotherapy. Biomaterials. 277:1211102021. View Article : Google Scholar : PubMed/NCBI

152 

Wu M, Xu LG, Li X, Zhai Z and Shu HB: AMID, an apoptosis-inducing factor-homologous mitochondrion-associated protein, induces caspase-independent apoptosis. J Biol Chem. 277:25617–25623. 2002. View Article : Google Scholar : PubMed/NCBI

153 

Ohiro Y, Garkavtsev I, Kobayashi S, Sreekumar KR, Nantz R, Higashikubo BT, Duffy SL, Higashikubo R, Usheva A, Gius D, et al: A novel p53-inducible apoptogenic gene, PRG3, encodes a homologue of the apoptosis-inducing factor (AIF). FEBS Lett. 524:163–171. 2002. View Article : Google Scholar : PubMed/NCBI

154 

Nakamura T, Mishima E, Yamada N, Mourão ASD, Trümbach D, Doll S, Wanninger J, Lytton E, Sennhenn P, Nishida Xavier da Silva T, et al: Integrated chemical and genetic screens unveil FSP1 mechanisms of ferroptosis regulation. Nat Struct Mol Biol. 30:1806–1815. 2023. View Article : Google Scholar : PubMed/NCBI

155 

Lv Y, Liang C, Sun Q, Zhu J, Xu H, Li X, Li YY, Wang Q, Yuan H, Chu B and Zhu D: Structural insights into FSP1 catalysis and ferroptosis inhibition. Nat Commun. 14:59332023. View Article : Google Scholar : PubMed/NCBI

156 

Deshwal S, Onishi M, Tatsuta T, Bartsch T, Cors E, Ried K, Lemke K, Nolte H, Giavalisco P and Langer T: Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7. Nat Cell Biol. 25:246–257. 2023.PubMed/NCBI

157 

Frei B, Kim MC and Ames BN: Ubiquinol-10 is an effective lipid-soluble antioxidant at physiological concentrations. Proc Natl Acad Sci USA. 87:4879–4883. 1990. View Article : Google Scholar : PubMed/NCBI

158 

Ernster L, Forsmark P and Nordenbrand K: The mode of action of lipid-soluble antioxidants in biological membranes. Relationship between the effects of ubiquinol and vitamin E as inhibitors of lipid peroxidation in submitochondrial particles. J Nutr Sci Vitaminol (Tokyo) Spec No. 548–551. 1992. View Article : Google Scholar : PubMed/NCBI

159 

Sharifi-Rad M, Anil Kumar NV, Zucca P, Varoni EM, Dini L, Panzarini E, Rajkovic J, Tsouh Fokou PV, Azzini E, Peluso I, et al: Lifestyle, oxidative stress, and antioxidants: Back and forth in the pathophysiology of chronic diseases. Front Physiol. 11:6942020. View Article : Google Scholar : PubMed/NCBI

160 

Wang Y and Hekimi S: Understanding ubiquinone. Trends Cell Biol. 26:367–378. 2016. View Article : Google Scholar : PubMed/NCBI

161 

Naguib YW, Saha S, Skeie JM, Acri T, Ebeid K, Abdel-Rahman S, Kesh S, Schmidt GA, Nishimura DY, Banas JA, et al: Solubilized ubiquinol for preserving corneal function. Biomaterials. 275:1208422021. View Article : Google Scholar : PubMed/NCBI

162 

Zameitat E, Freymark G, Dietz CD, Löffler M and Bölker M: Functional expression of human dihydroorotate dehydrogenase (DHODH) in pyr4 mutants of ustilago maydis allows target validation of DHODH inhibitors in vivo. Appl Environ Microbiol. 73:3371–3379. 2007. View Article : Google Scholar : PubMed/NCBI

163 

Reis RAG, Calil FA, Feliciano PR, Pinheiro MP and Nonato MC: The dihydroorotate dehydrogenases: Past and present. Arch Biochem Biophys. 632:175–191. 2017. View Article : Google Scholar : PubMed/NCBI

164 

Evans DR and Guy HI: Mammalian pyrimidine biosynthesis: Fresh insights into an ancient pathway. J Biol Chem. 279:33035–33038. 2004. View Article : Google Scholar : PubMed/NCBI

165 

Leban J, Kralik M, Mies J, Gassen M, Tentschert K and Baumgartner R: SAR, species specificity, and cellular activity of cyclopentene dicarboxylic acid amides as DHODH inhibitors. Bioorg Med Chem Lett. 15:4854–4857. 2005. View Article : Google Scholar : PubMed/NCBI

166 

Vyas VK and Ghate M: Recent developments in the medicinal chemistry and therapeutic potential of dihydroorotate dehydrogenase (DHODH) inhibitors. Mini Rev Med Chem. 11:1039–1055. 2011. View Article : Google Scholar : PubMed/NCBI

167 

Rodriguez JMO, Krupinska E, Wacklin-Knecht H and Knecht W: Preparation of human dihydroorotate dehydrogenase for interaction studies with lipid bilayers. Nucleosides Nucleotides Nucleic Acids. 39:1306–1319. 2020. View Article : Google Scholar : PubMed/NCBI

168 

Peeters MJW, Aehnlich P, Pizzella A, Mølgaard K, Seremet T, Met Ö, Rasmussen LJ, Thor Straten P and Desler C: Mitochondrial-linked de novo pyrimidine biosynthesis dictates human T-cell proliferation but not expression of effector molecules. Front Immunol. 12:7188632021. View Article : Google Scholar : PubMed/NCBI

169 

Martínez-Reyes I, Cardona LR, Kong H, Vasan K, McElroy GS, Werner M, Kihshen H, Reczek CR, Weinberg SE, Gao P, et al: Mitochondrial ubiquinol oxidation is necessary for tumour growth. Nature. 585:288–292. 2020. View Article : Google Scholar : PubMed/NCBI

170 

Yang C, Zhao Y, Wang L, Guo Z, Ma L, Yang R, Wu Y, Li X, Niu J, Chu Q, et al: De novo pyrimidine biosynthetic complexes support cancer cell proliferation and ferroptosis defence. Nat Cell Biol. 25:836–847. 2023. View Article : Google Scholar : PubMed/NCBI

171 

Mao C, Liu X, Zhang Y, Lei G, Yan Y, Lee H, Koppula P, Wu S, Zhuang L, Fang B, et al: DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature. 593:586–590. 2021. View Article : Google Scholar : PubMed/NCBI

172 

Ding Q, Tang W, Li X, Ding Y, Chen X, Cao W, Wang X, Mo W, Su Z, Zhang Q and Guo H: Mitochondrial-targeted brequinar liposome boosted mitochondrial-related ferroptosis for promoting checkpoint blockade immunotherapy in bladder cancer. J Control Release. 363:221–234. 2023. View Article : Google Scholar : PubMed/NCBI

173 

Wang F and Min J: DHODH tangoing with GPX4 on the ferroptotic stage. Signal Transduct Target Ther. 6:2442021. View Article : Google Scholar : PubMed/NCBI

174 

Diao J, Jia Y, Dai E, Liu J, Kang R, Tang D, Han L, Zhong Y and Meng L: Ferroptotic therapy in cancer: Benefits, side effects, and risks. Mol Cancer. 23:892024. View Article : Google Scholar : PubMed/NCBI

175 

Westphal S and Kalthoff H: Apoptosis: Targets in pancreatic cancer. Mol Cancer. 2:62003. View Article : Google Scholar : PubMed/NCBI

176 

Todaro M, Lombardo Y, Francipane MG, Alea MP, Cammareri P, Iovino F, Di Stefano AB, Di Bernardo C, Agrusa A, Condorelli G, et al: Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4. Cell Death Differ. 15:762–772. 2008. View Article : Google Scholar : PubMed/NCBI

177 

Miao Z, Xu L, Gu W, Ren Y, Li R, Zhang S, Chen C, Wang H, Ji J and Chen J: A targetable PRR11-DHODH axis drives ferroptosis- and temozolomide-resistance in glioblastoma. Redox Biol. 73:1032202024. View Article : Google Scholar : PubMed/NCBI

178 

Fanet H, Capuron L, Castanon N, Calon F and Vancassel S: Tetrahydrobioterin (BH4) pathway: From metabolism to neuropsychiatry. Curr Neuropharmacol. 19:591–609. 2021. View Article : Google Scholar : PubMed/NCBI

179 

Feng Y, Feng Y, Gu L, Liu P, Cao J and Zhang S: The critical role of tetrahydrobiopterin (BH4) metabolism in modulating radiosensitivity: BH4/NOS axis as an angel or a devil. Front Oncol. 11:7206322021. View Article : Google Scholar : PubMed/NCBI

180 

Burg AW and Brown GM: The biosynthesis of folic acid. 8. Purification and properties of the enzyme that catalyzes the production of formate from carbon atom 8 of guanosine triphosphate. J Biol Chem. 243:2349–2358. 1968. View Article : Google Scholar : PubMed/NCBI

181 

Niederwieser A, Staudenmann W and Wetzel E: High-performance liquid chromatography with column switching for the analysis of biogenic amine metabolites and pterins. J Chromatogr. 290:237–246. 1984. View Article : Google Scholar : PubMed/NCBI

182 

Jiang Y, Zhao J, Li R, Liu Y, Zhou L, Wang C, Lv C, Gao L and Cui D: CircLRFN5 inhibits the progression of glioblastoma via PRRX2/GCH1 mediated ferroptosis. J Exp Clin Cancer Res. 41:3072022. View Article : Google Scholar : PubMed/NCBI

183 

Liang D, Shu R, Jiang S, Gan Q, Wu S, Zhao Y, Yang L, Xu M, Gao J and Meng Y: Expression of BmDHFR is up-regulated to trigger an increase in the BH4/BH2 ratio when the de novo synthesis of BH4 is blocked in silkworm, Bombyx mori. Int J Biol Macromol. 225:625–633. 2023. View Article : Google Scholar : PubMed/NCBI

184 

Ebenhoch R, Bauer M, Reinert D, Kersting A, Huber S, Schmid A, Hinz I, Feiler M, Müller K and Nar H: Biophysical and structural investigation of the regulation of human GTP cyclohydrolase I by its regulatory protein GFRP. J Struct Biol. 213:1076912021. View Article : Google Scholar : PubMed/NCBI

185 

Kraft VAN, Bezjian CT, Pfeiffer S, Ringelstetter L, Müller C, Zandkarimi F, Merl-Pham J, Bao X, Anastasov N, Kössl J, et al: GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling. ACS Cent Sci. 6:41–53. 2020. View Article : Google Scholar : PubMed/NCBI

186 

Wang D, Liang W, Huo D, Wang H, Wang Y, Cong C, Zhang C, Yan S, Gao M, Su X, et al: SPY1 inhibits neuronal ferroptosis in amyotrophic lateral sclerosis by reducing lipid peroxidation through regulation of GCH1 and TFR1. Cell Death Differ. 30:369–382. 2023. View Article : Google Scholar : PubMed/NCBI

187 

Vasquez-Vivar J, Shi Z and Tan S: Tetrahydrobiopterin in cell function and death mechanisms. Antioxid Redox Signal. 37:171–183. 2022. View Article : Google Scholar : PubMed/NCBI

188 

Eichwald T, da Silva LDB, Staats Pires AC, Niero L, Schnorrenberger E, Filho CC, Espíndola G, Huang WL, Guillemin GJ, Abdenur JE and Latini A: Tetrahydrobiopterin: Beyond its traditional role as a cofactor. Antioxidants (Basel). 12:10372023. View Article : Google Scholar : PubMed/NCBI

189 

Villaume WA: Marginal BH4 deficiencies, iNOS, and self-perpetuating oxidative stress in post-acute sequelae of Covid-19. Med Hypotheses. 163:1108422022. View Article : Google Scholar : PubMed/NCBI

190 

Soula M, Weber RA, Zilka O, Alwaseem H, La K, Yen F, Molina H, Garcia-Bermudez J, Pratt DA and Birsoy K: Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers. Nat Chem Biol. 16:1351–1360. 2020. View Article : Google Scholar : PubMed/NCBI

191 

Xiao Y, Yuan Y, Yang Y, Liu B, Ding Z, Luo J, Chen S and Yu L: GCH1 reduces LPS-induced alveolar macrophage polarization and inflammation by inhibition of ferroptosis. Inflamm Res. 72:1941–1955. 2023. View Article : Google Scholar : PubMed/NCBI

192 

Famitafreshi H and Karimian M: Paradoxical regulation of iron in hippocampus and prefrontal cortex induces schizophrenic-like symptoms in male rats. Int J Neurosci. 130:384–390. 2020. View Article : Google Scholar : PubMed/NCBI

193 

Kim SW, Stewart R, Park WY, Jhon M, Lee JY, Kim SY, Kim JM, Amminger P, Chung YC and Yoon JS: Latent iron deficiency as a marker of negative symptoms in patients with first-episode schizophrenia spectrum disorder. Nutrients. 10:17072018. View Article : Google Scholar : PubMed/NCBI

194 

Wei N, Ju M, Su X, Zhang Y, Huang Y, Rao X, Cui L, Lin Z and Dong Y: Transplantation of gut microbiota derived from patients with schizophrenia induces schizophrenia-like behaviors and dysregulated brain transcript response in mice. Schizophrenia (Heidelb). 10:442024. View Article : Google Scholar : PubMed/NCBI

195 

Feng S, Chen J, Qu C, Yang L, Wu X, Wang S, Yang T, Liu H, Fang Y and Sun P: Identification of ferroptosis-related genes in schizophrenia based on bioinformatic analysis. Genes (Basel). 13:21682022. View Article : Google Scholar : PubMed/NCBI

196 

Liu X, Fan L, Lu C, Yin S and Hu H: Functional role of p53 in the regulation of chemical-induced oxidative stress. Oxid Med Cell Longev. 2020:60397692020.PubMed/NCBI

197 

Byeon SH, Lee SC, Choi SH, Lee HK, Lee JH, Chu YK and Kwon OW: Vascular endothelial growth factor as an autocrine survival factor for retinal pigment epithelial cells under oxidative stress via the VEGF-R2/PI3K/Akt. Invest Ophthalmol Vis Sci. 51:1190–1197. 2010. View Article : Google Scholar : PubMed/NCBI

198 

Martín-Vázquez E, Cobo-Vuilleumier N, López-Noriega L, Lorenzo PI and Gauthier BR: The PTGS2/COX2-PGE2 signaling cascade in inflammation: Pro or anti? A case study with type 1 diabetes mellitus. Int J Biol Sci. 19:4157–4165. 2023. View Article : Google Scholar : PubMed/NCBI

199 

Lian K, Li Y, Yang W, Ye J, Liu H, Wang T, Yang G, Cheng Y and Xu X: Hub genes, a diagnostic model, and immune infiltration based on ferroptosis-linked genes in schizophrenia. IBRO Neurosci Rep. 16:317–328. 2024. View Article : Google Scholar : PubMed/NCBI

200 

Feng Y and Shen J: Machine learning-based predictive models and drug prediction for schizophrenia in multiple programmed cell death patterns. Front Mol Neurosci. 16:11237082023. View Article : Google Scholar : PubMed/NCBI

201 

Zhang D, Wu X, Xue X, Li W, Zhou P, Lv Z, Zhao K and Zhu F: Ancient dormant virus remnant ERVW-1 drives ferroptosis via degradation of GPX4 and SLC3A2 in schizophrenia. Virol Sin. 39:31–43. 2024. View Article : Google Scholar : PubMed/NCBI

202 

Ursini F and Maiorino M: Lipid peroxidation and ferroptosis: The role of GSH and GPx4. Free Radic Biol Med. 152:175–185. 2020. View Article : Google Scholar : PubMed/NCBI

203 

Forcina GC and Dixon SJ: GPX4 at the crossroads of lipid homeostasis and ferroptosis. Proteomics. 19:e18003112019. View Article : Google Scholar : PubMed/NCBI

204 

Casanova MF, Crapanzano KA, Mannheim G and Kruesi M: Sydenham's chorea and schizophrenia: A case report. Schizophr Res. 16:73–76. 1995. View Article : Google Scholar : PubMed/NCBI

205 

Casanova MF, Comparini SO, Kim RW and Kleinman JE: Staining intensity of brain iron in patients with schizophrenia: A postmortem study. J Neuropsychiatry Clin Neurosci. 4:36–41. 1992. View Article : Google Scholar : PubMed/NCBI

206 

Madden DJ and Merenstein JL: Quantitative susceptibility mapping of brain iron in healthy aging and cognition. Neuroimage. 282:1204012023. View Article : Google Scholar : PubMed/NCBI

207 

Ravanfar P, Syeda WT, Jayaram M, Rushmore RJ, Moffat B, Lin AP, Lyall AE, Merritt AH, Yaghmaie N, Laskaris L, et al: In vivo 7-tesla MRI investigation of brain iron and its metabolic correlates in chronic schizophrenia. Schizophrenia (Heidelb). 8:862022. View Article : Google Scholar : PubMed/NCBI

208 

Sonnenschein SF, Parr AC, Larsen B, Calabro FJ, Foran W, Eack SM, Luna B and Sarpal DK: Subcortical brain iron deposition in individuals with schizophrenia. J Psychiatr Res. 151:272–278. 2022. View Article : Google Scholar : PubMed/NCBI

209 

Cao B, Yan L, Ma J, Jin M, Park C, Nozari Y, Kazmierczak OP, Zuckerman H, Lee Y, Pan Z, et al: Comparison of serum essential trace metals between patients with schizophrenia and healthy controls. J Trace Elem Med Biol. 51:79–85. 2019. View Article : Google Scholar : PubMed/NCBI

210 

Santa Cruz EC, Madrid KC, Arruda MAZ and Sussulini A: Association between trace elements in serum from bipolar disorder and schizophrenia patients considering treatment effects. J Trace Elem Med Biol. 59:1264672020. View Article : Google Scholar : PubMed/NCBI

211 

Owiredu WKBA, Brenya PK, Osei Y, Laing EF, Okrah CO, Obirikorang C, Anto EO, Acheampong E and Donkor S: Evaluation of serum iron overload, AST:ALT ratio and log10ferritin:AST ratio among schizophrenia patients in the Kumasi Metropolis, Ghana: A case-control study. BMC Res Notes. 12:8022019. View Article : Google Scholar : PubMed/NCBI

212 

Kumar J, Liddle EB, Fernandes CC, Palaniyappan L, Hall EL, Robson SE, Simmonite M, Fiesal J, Katshu MZ, Qureshi A, et al: Glutathione and glutamate in schizophrenia: A 7T MRS study. Mol Psychiatry. 25:873–882. 2020. View Article : Google Scholar : PubMed/NCBI

213 

Nucifora LG, Tanaka T, Hayes LN, Kim M, Lee BJ, Matsuda T, Nucifora FC Jr, Sedlak T, Mojtabai R, Eaton W and Sawa A: Reduction of plasma glutathione in psychosis associated with schizophrenia and bipolar disorder in translational psychiatry. Transl Psychiatry. 7:e12152017. View Article : Google Scholar : PubMed/NCBI

214 

Tenório MCDS, Graciliano NG, Moura FA, de Oliveira ACM and Goulart MOF: N-acetylcysteine (NAC): Impacts on human health. Antioxidants (Basel). 10:9672021. View Article : Google Scholar : PubMed/NCBI

215 

Raghu G, Berk M, Campochiaro PA, Jaeschke H, Marenzi G, Richeldi L, Wen FQ, Nicoletti F and Calverley PMA: The multifaceted therapeutic role of N-acetylcysteine (NAC) in disorders characterized by oxidative stress. Curr Neuropharmacol. 19:1202–1224. 2021. View Article : Google Scholar : PubMed/NCBI

216 

das Neves Duarte JM, Kulak A, Gholam-Razaee MM, Cuenod M, Gruetter R and Do KQ: N-acetylcysteine normalizes neurochemical changes in the glutathione-deficient schizophrenia mouse model during development. Biol Psychiatry. 71:1006–1014. 2012. View Article : Google Scholar : PubMed/NCBI

217 

Berk M, Copolov DL, Dean O, Lu K, Jeavons S, Schapkaitz I, Anderson-Hunt M and Bush AI: N-acetyl cysteine for depressive symptoms in bipolar disorder-a double-blind randomized placebo-controlled trial. Biol Psychiatry. 64:468–475. 2008. View Article : Google Scholar : PubMed/NCBI

218 

Conus P, Seidman LJ, Fournier M, Xin L, Cleusix M, Baumann PS, Ferrari C, Cousins A, Alameda L, Gholam-Rezaee M, et al: N-acetylcysteine in a double-blind randomized placebo-controlled trial: Toward biomarker-guided treatment in early psychosis. Schizophr Bull. 44:317–327. 2018. View Article : Google Scholar : PubMed/NCBI

219 

Rapado-Castro M, Dodd S, Bush AI, Malhi GS, Skvarc DR, On ZX, Berk M and Dean OM: Cognitive effects of adjunctive N-acetyl cysteine in psychosis. Psychol Med. 47:866–876. 2017. View Article : Google Scholar : PubMed/NCBI

220 

Sepehrmanesh Z and Heidary M, Akasheh N, Akbari H and Heidary M: Therapeutic effect of adjunctive N-acetyl cysteine (NAC) on symptoms of chronic schizophrenia: A double-blind, randomized clinical trial. Prog Neuropsychopharmacol Biol Psychiatry. 82:289–296. 2018. View Article : Google Scholar : PubMed/NCBI

221 

Farokhnia M, Azarkolah A, Adinehfar F, Khodaie-Ardakani MR, Hosseini SM, Yekehtaz H, Tabrizi M, Rezaei F, Salehi B, Sadeghi SM, et al: N-acetylcysteine as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia: A randomized, double-blind, placebo-controlled study. Clin Neuropharmacol. 36:185–192. 2013. View Article : Google Scholar : PubMed/NCBI

222 

Breier A, Liffick E, Hummer TA, Vohs JL, Yang Z, Mehdiyoun NF, Visco AC, Metzler E, Zhang Y and Francis MM: Effects of 12-month, double-blind N-acetyl cysteine on symptoms, cognition and brain morphology in early phase schizophrenia spectrum disorders. Schizophr Res. 199:395–402. 2018. View Article : Google Scholar : PubMed/NCBI

223 

Medvedev ON, Berk M, Dean OM, Brown E, Sandham MH, Dipnall JF, McNamara RK, Sumich A, Krägeloh CU, Narayanan A and Siegert RJ: A novel way to quantify schizophrenia symptoms in clinical trials. Eur J Clin Invest. 51:e133982021. View Article : Google Scholar : PubMed/NCBI

224 

Rossell SL, Francis PS, Galletly C, Harris A, Siskind D, Berk M, Bozaoglu K, Dark F, Dean O, Liu D, et al: N-acetylcysteine (NAC) in schizophrenia resistant to clozapine: A double blind randomised placebo controlled trial targeting negative symptoms. BMC Psychiatry. 16:3202016. View Article : Google Scholar : PubMed/NCBI

225 

Lavoie S, Murray MM, Deppen P, Knyazeva MG, Berk M, Boulat O, Bovet P, Bush AI, Conus P, Copolov D, et al: Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients. Neuropsychopharmacology. 33:2187–2199. 2008. View Article : Google Scholar : PubMed/NCBI

226 

Carmeli C, Knyazeva MG, Cuénod M and Do KQ: Glutathione precursor N-acetyl-cysteine modulates EEG synchronization in schizophrenia patients: A double-blind, randomized, placebo-controlled trial. PLoS One. 7:e293412012. View Article : Google Scholar : PubMed/NCBI

227 

Naguy A and Naguy C: N-acetyl-cysteine in schizophrenia-there is more than meets the eyes! CNS Spectr. 26:446–447. 2021. View Article : Google Scholar : PubMed/NCBI

228 

Deepmala Slattery J, Kumar N, Delhey L, Berk M, Dean O, Spielholz C and Frye R: Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review. Neurosci Biobehav Rev. 55:294–321. 2015. View Article : Google Scholar : PubMed/NCBI

229 

Dean O, Giorlando F and Berk M: N-acetylcysteine in psychiatry: Current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci. 36:78–86. 2011. View Article : Google Scholar : PubMed/NCBI

230 

Klauser P, Xin L, Fournier M, Griffa A, Cleusix M, Jenni R, Cuenod M, Gruetter R, Hagmann P, Conus P, et al: N-acetylcysteine add-on treatment leads to an improvement of fornix white matter integrity in early psychosis: A double-blind randomized placebo-controlled trial. Transl Psychiatry. 8:2202018. View Article : Google Scholar : PubMed/NCBI

231 

Tharoor H, Mara S and Gopal S: Role of novel dietary supplement N-acetyl cysteine in treating negative symptoms in schizophrenia: A 6-month follow-up study. Indian J Psychol Med. 40:139–142. 2018. View Article : Google Scholar : PubMed/NCBI

232 

Tiihonen J, Tanskanen A and Taipale H: 20-Year nationwide follow-up study on discontinuation of antipsychotic treatment in first-episode schizophrenia. Am J Psychiatry. 175:765–773. 2018. View Article : Google Scholar : PubMed/NCBI

233 

Bjørklund G, Shanaida M, Lysiuk R, Antonyak H, Klishch I, Shanaida V and Peana M: Selenium: An antioxidant with a critical role in anti-aging. Molecules. 27:66132022. View Article : Google Scholar : PubMed/NCBI

234 

Brown JS Jr: Role of selenium and other trace elements in the geography of schizophrenia. Schizophr Bull. 20:387–398. 1994. View Article : Google Scholar : PubMed/NCBI

235 

Deng MG, Cui HT, Nie JQ, Liang Y and Chai C: Genetic association between circulating selenium level and the risk of schizophrenia in the European population: A two-sample Mendelian randomization study. Front Nutr. 9:9698872022. View Article : Google Scholar : PubMed/NCBI

236 

Cai L, Chen T, Yang J, Zhou K, Yan X, Chen W, Sun L, Li L, Qin S, Wang P, et al: Serum trace element differences between schizophrenia patients and controls in the Han Chinese population. Sci Rep. 5:150132015. View Article : Google Scholar : PubMed/NCBI

237 

Mattmiller SA, Carlson BA and Sordillo LM: Regulation of inflammation by selenium and selenoproteins: Impact on eicosanoid biosynthesis. J Nutr Sci. 2:e282013. View Article : Google Scholar : PubMed/NCBI

238 

Soares de Oliveira AR, Jayanne Clímaco Cruz K, Beatriz Silva Morais J, Rocha Dos Santos L, Rodrigues de Sousa Melo S, Fontenelle LC, Santos de Sousa G, Costa Maia CS, Oliveira Duarte de Araújo C, Leal Mendes I, et al: Selenium status and oxidative stress in obese: Influence of adiposity. Eur J Clin Invest. 51:e135382021. View Article : Google Scholar : PubMed/NCBI

239 

Rayman MP: The importance of selenium to human health. Lancet. 356:233–241. 2000. View Article : Google Scholar : PubMed/NCBI

240 

Li Z, Liu Y, Li X, Ju W, Wu G, Yang X, Fu X and Gao X: Association of elements with schizophrenia and intervention of selenium supplements. Biol Trace Elem Res. 183:16–21. 2018. View Article : Google Scholar : PubMed/NCBI

241 

Jamilian H and Ghaderi A: The effects of probiotic and selenium co-supplementation on clinical and metabolic scales in chronic schizophrenia: A randomized, double-blind, placebo-controlled trial. Biol Trace Elem Res. 199:4430–4438. 2021. View Article : Google Scholar : PubMed/NCBI

242 

Calder PC: Omega-3 fatty acids and inflammatory processes. Nutrients. 2:355–374. 2010. View Article : Google Scholar : PubMed/NCBI

243 

Djuricic I and Calder PC: Beneficial outcomes of omega-6 and omega-3 polyunsaturated fatty acids on human health: An update for 2021. Nutrients. 13:24212021. View Article : Google Scholar : PubMed/NCBI

244 

Tang W, Wang Y, Xu F, Fan W, Zhang Y, Fan K, Wang W, Zhang Y and Zhang C: Omega-3 fatty acids ameliorate cognitive dysfunction in schizophrenia patients with metabolic syndrome. Brain Behav Immun. 88:529–534. 2020. View Article : Google Scholar : PubMed/NCBI

245 

Hsu MC, Huang YS and Ouyang WC: Beneficial effects of omega-3 fatty acid supplementation in schizophrenia: Possible mechanisms. Lipids Health Dis. 19:1592020. View Article : Google Scholar : PubMed/NCBI

246 

Hsu MC and Ouyang WC: A systematic review of effectiveness of omega-3 fatty acid supplementation on symptoms, social functions, and neurobiological variables in schizophrenia. Biol Res Nurs. 23:723–737. 2021. View Article : Google Scholar : PubMed/NCBI

247 

Goh KK, Chen CYA, Chen CH and Lu ML: Effects of omega-3 polyunsaturated fatty acids supplements on psychopathology and metabolic parameters in schizophrenia: A meta-analysis of randomized controlled trials. J Psychopharmacol. 35:221–235. 2021. View Article : Google Scholar : PubMed/NCBI

248 

Surette ME: The science behind dietary omega-3 fatty acids. CMAJ. 178:177–180. 2008. View Article : Google Scholar : PubMed/NCBI

249 

Fuentes NR, Kim E, Fan YY and Chapkin RS: Omega-3 fatty acids, membrane remodeling and cancer prevention. Mol Aspects Med. 64:79–91. 2018. View Article : Google Scholar : PubMed/NCBI

250 

Joffre C, Rey C and Layé S: N-3 polyunsaturated fatty acids and the resolution of neuroinflammation. Front Pharmacol. 10:10222019. View Article : Google Scholar : PubMed/NCBI

251 

Chen Y, Fang ZM, Yi X, Wei X and Jiang DS: The interaction between ferroptosis and inflammatory signaling pathways. Cell Death Dis. 14:2052023. View Article : Google Scholar : PubMed/NCBI

252 

Simopoulos AP: Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr. 21:495–505. 2002. View Article : Google Scholar : PubMed/NCBI

253 

Gutiérrez S, Svahn SL and Johansson ME: Effects of omega-3 fatty acids on immune cells. Int J Mol Sci. 20:50282019. View Article : Google Scholar : PubMed/NCBI

254 

Nuñez MT and Chana-Cuevas P: New perspectives in iron chelation therapy for the treatment of neurodegenerative diseases. Pharmaceuticals (Basel). 11:1092018. View Article : Google Scholar : PubMed/NCBI

255 

Devos D, Labreuche J, Rascol O, Corvol JC, Duhamel A, Guyon Delannoy P, Poewe W, Compta Y, Pavese N, Růžička E, et al: Trial of deferiprone in Parkinson's disease. N Engl J Med. 387:2045–2055. 2022. View Article : Google Scholar : PubMed/NCBI

256 

Urrutia PJ, Bórquez DA and Núñez MT: Inflaming the brain with Iron. Antioxidants (Basel). 10:612021. View Article : Google Scholar : PubMed/NCBI

257 

Costa I, Barbosa DJ, Benfeito S, Silva V, Chavarria D, Borges F, Remião F and Silva R: Molecular mechanisms of ferroptosis and their involvement in brain diseases. Pharmacol Ther. 244:1083732023. View Article : Google Scholar : PubMed/NCBI

258 

Ramadhan MIA, Sitanaya SN, Hakim AHW and Ramli Y: The role of iron-chelating therapy in improving neurological outcome in patients with intracerebral hemorrhage: Evidence-based case report. Medicina (Kaunas). 59:4532023. View Article : Google Scholar : PubMed/NCBI

259 

Dusek P, Schneider SA and Aaseth J: Iron chelation in the treatment of neurodegenerative diseases. J Trace Elem Med Biol. 38:81–92. 2016. View Article : Google Scholar : PubMed/NCBI

260 

Cutler P: Iron overload and psychiatric illness. Can J Psychiatry. 39:8–11. 1994. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

February-2025
Volume 31 Issue 2

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

  • Journal Metrics
  • Impact Factor: 3.4
  • Ranked Medicine Research and Experimental
    (total number of cites)
  • CiteScore: 7.6
  • CiteScore Rank: Q1: #82/347 Biochemistry, Genetics and Molecular Biology
  • Source Normalized Impact per Paper (SNIP): 0.647
  • SCImago Journal Rank (SJR): 0.781
International Symposium on Molecular Medicine Conference Banner
The Cancer Story
World Congress on Advances in Oncology and International Symposium on Molecular Medicine Conference Banner
World Academy Of Sciences Banner
Heyday Road Banner

0

Copy and paste a formatted citation
x
Spandidos Publications style
Lv S and Luo C: Ferroptosis in schizophrenia: Mechanisms and therapeutic potentials (Review). Mol Med Rep 31: 37, 2025.
APA
Lv, S., & Luo, C. (2025). Ferroptosis in schizophrenia: Mechanisms and therapeutic potentials (Review). Molecular Medicine Reports, 31, 37. https://doi.org/10.3892/mmr.2024.13402
MLA
Lv, S., Luo, C."Ferroptosis in schizophrenia: Mechanisms and therapeutic potentials (Review)". Molecular Medicine Reports 31.2 (2025): 37.
Chicago
Lv, S., Luo, C."Ferroptosis in schizophrenia: Mechanisms and therapeutic potentials (Review)". Molecular Medicine Reports 31, no. 2 (2025): 37. https://doi.org/10.3892/mmr.2024.13402