The Glutamate–Glutathione axis in neuropsychiatric disorders and cancer: From shared mechanisms to non-invasive biomarkers

Rui Wang; Yanfei Li; Dafa Shi; Hongying Huang; Zhongruowen Ren; Yuxi Ge; Yongmin Chang; Gen Yan

doi:10.1016/j.redox.2026.104215

. 2026 May 15;94:104215. doi: 10.1016/j.redox.2026.104215

The Glutamate–Glutathione axis in neuropsychiatric disorders and cancer: From shared mechanisms to non-invasive biomarkers

Rui Wang ^a,¹, Yanfei Li ^b,¹, Dafa Shi ^a,^c, Hongying Huang ^a,^c, Zhongruowen Ren ^a,^d, Yuxi Ge ^e, Yongmin Chang ^f,^g,^⁎, Gen Yan ^a,^⁎⁎

PMCID: PMC13197713 PMID: 42143971

Abstract

Glutamate is the most abundant excitatory neurotransmitter in the central nervous system and a key non-essential amino acid in the body. It plays a central role in maintaining the excitatory-inhibitory balance of the nervous system, regulating systemic metabolic homeostasis, and participating in immune modulation. Additionally, it serves as a precursor for glutathione synthesis. Glutathione is a vital antioxidant and detoxifying molecule in organisms, capable of directly scavenging reactive oxygen species or toxic metabolites. Dysfunction of glutathione is associated with oxidative stress-related diseases. Given the critical roles of glutamate and glutathione in physiological and pathological states, we aim to systematically elucidates the metabolic interplay between glutamate and glutathione, referred to here as the Glutamate-Glutathione axis, as an integrative conceptual framework grounded in established biochemistry. By detailing the metabolic interplay of glutamate and glutathione, this review explores their mutually influential mechanisms. Furthermore, it summarizes the relevant signaling pathways and regulatory mechanisms within the Glutamate-Glutathione axis, clarifying its pivotal role in disease pathogenesis, with a particular focus on neuropsychiatric disorders and cancer. Finally, we aim to review non-invasive methods for detecting glutamate and glutathione using magnetic resonance imaging and presents our specialized sequence. This approach aims to provide a valuable non-invasive imaging tool for early diagnosis, efficacy evaluation, and therapeutic target development in related diseases. By integrating foundational metabolic networks, molecular regulatory mechanisms, disease associations, and clinical detection techniques, this review aim to establish the research framework of the Glutamate-Glutathione axis, fostering deeper integration and advancement from bench to bedside in this field.

Keywords: Glutamate, Glutathione, Neuropsychiatric disorders, Cancer, MEGA-PRESS

Graphical abstract

Highlights

•
Introduces the Glu-GSH axis as an integrative metabolic-redox framework.
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Identifies key signaling networks governing Glu-GSH axis regulation.
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Links Glu-GSH dysregulation to neuropsychiatric disorders and cancer.
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Proposes the Glu-GSH axis as an early biomarker for brain and metabolic diseases.
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Demonstrates in vivo Glu-GSH detection via MEGA-PRESS with original data.

1. Introduction

Glutamate, a non-essential amino acid, represents the most abundant excitatory neurotransmitter and a pivotal metabolic intermediate in mammals [1]. Chemically, it is an α-amino glutaric acid characterized by the presence of two carboxyl groups (-COOH) and one amino group (-NH2), classifying it as an acidic amino acid [2]. Glutamate exists in both free and bound forms. The free form acts as a neurotransmitter or intracellular metabolite [3], whereas the bound form is incorporated into proteins or serves as a precursor for glutathione and γ-aminobutyric acid (GABA) [4],etc. Given its ubiquitous presence in living organisms, glutamate exerts a multitude of critical effects. When it is mentioned in the central nervous system (CNS), glutamate serves as the major excitatory neurotransmitter. By binding to its receptors, it regulates synaptic transmission and is critically involved in various neurophysiological processes such as learning and memory [5,6]. Furthermore, glutamate contributes to neuronal differentiation, migration, and survival, playing an essential role in neural development [7]. However, excessive glutamate release can induce neurotoxicity, a condition termed “glutamate excitotoxicity”, which is implicated in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and ischemic brain injury [8,9]. In cellular metabolic homeostasis, glutamate serves as a precursor of α-ketoglutarate (α-KG), which enters the tricarboxylic acid (TCA) cycle to support cellular energy production [10]. It also acts as a fundamental precursor for the biosynthesis of various metabolites, including GABA and glutathione, thereby bridging protein synthesis and broader amino acid metabolism [11]. Notably, metabolic reprogramming of glutamate supports tumor growth and proliferation, facilitating cancer progression [10]. In the liver, glutamate is converted to glutamine via glutamine synthase, a critical step in the detoxification of ammonia [12]. In the immune system, glutamate can modulate immune cell activation by interacting with receptors expressed on the cell surface [13,14]. Furthermore, it regulates the downstream activity of signal pathways [15].

Glutathione is a tripeptide composed of glutamate, cysteine, and glycine [16]. It is ubiquitously present in mammalian tissues and cells, with cellular concentrations typically ranging from 1 to 10 mM. Notably, hepatocytes exhibit the highest concentrations, reaching 5-10 mM [17]. As one of the most critical intracellular antioxidants and detoxifying molecules, glutathione exists in two primary forms: reduced glutathione (GSH) and oxidized glutathione (GSSG) [18]. GSH accounts for over 98% of the total glutathione pool and serves as a direct participant in antioxidant reactions, during which it is converted to its oxidized form [19]. GSSG, present at relatively low levels, can be regenerated back to GSH by glutathione reductase. In antioxidant defense system, GSH serves as a vital intracellular antioxidant. It maintains cellular redox homeostasis through the dynamic interconversion between its reduced and oxidized forms [20]. GSH directly neutralizes reactive oxygen species (ROS), thereby protecting cells from oxidative stress damage [21]. Furthermore, GSH interacts with disulfide bonds in proteins, playing a crucial role in maintaining proper protein folding and function [22]. In metabolic homeostasis, GSH participates in various intracellular metabolic pathways, including amino acid metabolism [23], fatty acid metabolism [24] and glucose metabolism [25]. It also modulates the cellular redox state, thereby influencing multiple signal transduction pathways [26]. Additionally, GSH contributes to drug metabolism by conjugating with pharmaceuticals or their metabolites, facilitating their excretion [27]. Similarly, it binds to toxins such as heavy metals and free radicals, forming soluble complexes that promote detoxification and elimination [28]. Within the immune system, GSH plays a regulatory role in the activity of T cells, B cells, and macrophages, significantly influencing their proliferation, differentiation, and effector functions [[29], [30], [31]]. Like glutamate, GSH is also involved in modulating inflammatory responses by regulating inflammatory cells and cytokine secretion [32,33].

Given that both of them play important roles in various pathophysiological processes such as neural injury, metabolic homeostasis, and immune regulation, existing literature has studied them relatively independently, without linking their balance to diseases. Importantly, the rationale for examining both neuropsychiatric disorders and cancer within a single review is supported by converging evidence from the emerging field of Cancer Neuroscience. Landmark studies have demonstrated that neurons form functional glutamatergic synapses with glioma cells, and that neuronal activity directly drives glioma proliferation and invasion through AMPA receptor-mediated glutamate release [34] These findings contributed to the formal establishment of Cancer Neuroscience as a distinct research discipline [35], which has since been systematically elaborated and has matured from an emerging concept into an independent field [36,37]. Besides, large-scale epidemiological data demonstrate that depression and anxiety are associated with a 13% increased risk of cancer incidence and a 21% increased risk of cancer-specific mortality [38]. Therefore, we aim to start from the intersection of glutamate and GSH metabolic pathways, explore the specific processes of their interconversion, investigate the roles of related signal pathways in these processes, and analyze their implications in typical diseases. Finally, we attempt to propose the concept of the metabolic interplay between glutamate and GSH (Glu-GSH axis), and a non-invasive detection method based on this concept might be employed to quantitatively measure the levels of glutamate and GSH, assessing whether the Glu-GSH axis can characterize disease progression.

2. Metabolic networks of glutamate and GSH: from biosynthesis to interconversion

2.1. The γ-glutamyl cycle: central metabolic hub

The γ-glutamyl cycle was first proposed by Professor Alton Meister in 1973 [39]. According to this model, GSH facilitates amino acid uptake and cellular transport. This cycle represents the core metabolic interaction linking glutamate and GSH metabolism. Its intermediate products simultaneously link glutamate metabolic pathways with GSH synthesis and degradation routes. Consequently, the intracellular levels of both glutamate and GSH are critically influenced by the dynamics of the γ-glutamyl cycle.

γ-Glutamyl transferase (GGT) is a heterodimeric glycoprotein composed of two subunits. The larger subunit has a molecular weight ranging from 38 to 72 kDa, while the smaller subunit varies between 20 and 66 kDa [40]. Within the γ-glutamyl cycle, GSH is released extracellularly, where the ectoenzyme GGT catalyzes the transfer of the γ-glutamyl group from GSH to an acceptor amino acid, generating γ-glutamyl-amino acid and cysteinylglycine. The γ-glutamyl-amino acid is transported back into the cell and further metabolized to release the acceptor amino acid and 5-oxoproline, the latter being convertible to glutamate for subsequent GSH synthesis. Meanwhile, cysteinylglycine is hydrolyzed by dipeptidase into cysteine and glycine [41]. Most cells efficiently take up cysteine, which is primarily utilized for GSH synthesis upon entering the cell. A portion contributes to protein synthesis, and the remainder is degraded to sulfate and taurine [17]. Under conditions of oxidative stress, particularly in metabolically active tumor cells, GGT expression is significantly upregulated [42] (Fig. 1).

Fig. 1 — γ-glutamyl cycle. GSH is transported extracellularly, where the extracellular enzyme GGT transfers the γ-glutamyl group of GSH to an amino acid, forming γ-glutamyl amino acid and cysteinylglycine. Subsequently, γ-glutamyl amino acid can be transported back into the cell and further metabolized intracellularly, releasing the amino acid and 5-oxoproline. 5-oxoproline can be converted to glutamate and reincorporated into GSH synthesis. Cysteinylglycine is cleaved by dipeptidase into cysteine and glycine, both of which are also transported back into the cell for re-synthesis of GSH. Most of the imported cysteine is utilized for GSH synthesis, while the remainder participates in the synthesis of new proteins and/or is broken down into sulfate and taurine. (GSH: glutathione, GGT: γ-glutamyl transferase, X_c⁻: glutamate/cystine antiporter).

Under physiological conditions, GGT within the γ-glutamyl cycle catalyzes the transfer of the γ-glutamyl group from GSH to acceptor amino acids, forming γ-glutamyl-amino acids. This reaction facilitates the transmembrane transport of amino acids, thereby not only promoting cellular amino acid uptake but also contributing to the regulation of intracellular amino acid homeostasis [43]. Furthermore, the γ-glutamyl cycle helps maintain intracellular redox balance by modulating GSH levels, thereby protecting cells from oxidative stress damage [17]. Additionally, this cycle participates in energy metabolism and supports protein synthesis processes [44].

In neurological disorders, the γ-glutamyl cycle exerts a dual influence: it modulates oxidative stress and neuroinflammation by regulating GSH levels [45], while simultaneously contributing to glutamate excitotoxicity, which exacerbates neuronal damage [46]. In metabolic diseases such as alcoholic liver disease, elevated activity of GGT within this cycle disrupts the glutamate-GSH balance, thereby aggravating hepatic injury [47]. In cancers, elevated GSH levels are associated with resistance to chemotherapy and radiotherapy. The γ-glutamyl cycle supports tumor cell survival by regulating GSH metabolism, enhancing the capacity to counteract oxidative stress, and consequently promoting tumor progression and treatment resistance [48].

2.2. Metabolism of glutamate

Glutamate biosynthesis primarily occurs through the following pathways: 1) From glucose-derived α-KG: α-KG, an intermediate of the TCA cycle ultimately derived from glucose metabolism, undergoes reductive amination catalyzed by glutamate dehydrogenase (GDH) to form glutamate. This process represents the principal route for glutamate synthesis in neurons and glial cells, relies heavily on mitochondrial energy metabolism, and is impaired under hypoxia or glycolytic dysfunction [49]. 2) From glutamine: glutamine is hydrolyzed by glutaminase (GLS) to produce glutamate and ammonia. This reaction serves as a critical complementary pathway, particularly when rapid glutamate synthesis is required, and accounts for over 60% of synaptically released glutamate, constituting the major source of neurotransmitter glutamate [50]. 3)From aspartate:aspartate donates its amino group to α-KG via aspartate transaminase, generating oxaloacetate and glutamate. 4) From alanine:alanine, under the action of alanine transaminase, transfers its amino group to α-KG, producing glutamate.

Neurons and astrocytes operate in close collaboration through a process known as the glutamate/GABA-glutamine cycle, which is essential for sustaining glutamate. In this cycle, Glutamine serves as the precursor of glutamate, which is synthesized and released by astrocytes then it is taken up by neurons to replenish the pools of glutamate and GABA. GABA is the main inhibitory neurotransmitter in the CNS, and glutamate is a metabolic precursor for GABA. Glutamate decarboxylase, predominantly located in neurons, catalyzes the decarboxylation of glutamate to GABA, a reaction is essential for maintaining the balance between excitatory and inhibitory neurotransmission in the CNS. GABA is subsequently catabolized via the GABA shunt: it is converted to succinic semialdehyde by GABA transaminase, and then to succinate by succinic semialdehyde dehydrogenase (SSADH), entering the TCA cycles as succinate. Notably, GABA catabolism does not regenerate glutamate directly, the carbon skeleton of GABA re-enters central metabolism exclusively through the TCA cycle as succinate [51]. Following synaptic release, glutamate is primarily removed from the cleft by uptake into astrocytes through glutamate transporter excitatory amino acid transporter (EAAT). Critically, astrocytes exclusively express glutamine synthase, the enzyme that catalyzes the conversion of glutamate into glutamine [52]. Thus, the glutamate/GABA-glutamine cycle represents a major metabolic flux in the brain and clearly illustrates the interaction between neurons and astrocytes in regulating glutamate (Fig. 2).

Fig. 2 — The glutamate/GABA-glutamine cycle. The glutamate/GABA-glutamine cycle is a critical metabolic coupling between neurons and astrocytes in the brain. The excitatory neurotransmitter glutamate or the inhibitory neurotransmitter GABA, released by neurons, is taken up by astrocytes and converted into glutamine within the cells via the enzyme glutamine synthetase. Glutamine is subsequently released and transported back into neurons, where it is resynthesized into glutamate or GABA, thereby completing the recycling and reuse of neurotransmitters. (Glu: glutamate, mGluR: metabotropic glutamate receptor, NMDAR: N-methyl-d-aspartate acid receptor, AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid Receptor, SAT2: System A neutral Amino Acid Transporter 2, EAAT: excitatory amino acid transporter, Gln: glutamine, SSA: succinic semialdehyde, SSADH: succinic semialdehyde dehydrogenase, Suc: succinate, SN1: System N1 Sodium-Coupled Neutral Amino Acid Transporter 1, α-KG: α-ketoglutarate, GAT: Gamma-Aminobutyric Acid Transporter, GABA: Gamma-Aminobutyric Acid, GABA_BR: Gamma-Aminobutyric Acid Type B Receptor, GABA_AR: Gamma-Aminobutyric Acid Type A Receptor).

2.3. Metabolism of GSH

GSH synthesis occurs via two sequential ATP-dependent steps: First, the γ-carboxyl group of glutamate and cysteine are conjugated by glutamate-cysteine ligase (GCL) to form γ-glutamylcysteine. Second, GSH synthetase (GS) catalyzes the linkage between the carboxyl group of γ-glutamylcysteine and the amino group of glycine, yielding GSH. GCL is a heterodimeric enzyme, comprising a 73 kDa catalytic subunit (GCLC) and a 31 kDa modifier subunit (GCLM) [53]. As the first rate-limiting enzyme in GSH synthesis, GCL activity is subject to negative feedback regulation by intracellular GSH levels [17] and positive feedback regulation under oxidative stress [54]. GS serves as the second rate-limiting enzyme. Its activity can be enhanced by oxidative stress but is not inhibited by intracellular GSH levels [18]. Overexpression of GS does not elevate cellular GSH levels, whereas GS deficiency leads to reduced GSH concentrations and subsequent metabolic disturbances [55].

Critically, GSH synthesis is highly dependent on cysteine availability. The extracellular Cys/CySS (cysteine/cystine) redox couple represents the principal determinant of cysteine supply to cells [56]: extracellular cystine is imported via the system X_c⁻ transporter, reduced intracellularly to cysteine, and channeled into GSH synthesis — making cystine import, rather than glutamate availability, the rate-limiting step for GSH production in most cell types [57]. Furthermore, GSH exists in distinct subcellular compartments with independently regulated pools [58]: approximately 80-85% in the cytoplasm, 10-15% in mitochondria, and the remainder in the endoplasmic reticulum. Each pool serves distinct functions — mitochondrial GSH is critical for mitochondrial redox homeostasis and protection against apoptosis [59], while ER-localized GSH governs oxidative protein folding via protein disulfide isomerase (PDI) activity [60]. Besides, GSH plays a central role in protein thiol redox regulation through S-glutathionylation, the reversible conjugation of GSH to reactive protein cysteine residues. Quantitative proteomics studies have demonstrated that, under basal conditions, the steady-state level of S-glutathionylated protein (PSSG) is extremely low (<0.1% of total protein cysteines), yet can increase dramatically (>15%) upon oxidative stress, underscoring the dynamic and sentinel role of GSH-dependent thiol modifications in cellular stress responses [61].

Intracellular GSH homeostasis is primarily maintained through a redox cycle: GSH acts as an electron donor, reducing peroxides to H₂O under the catalysis of glutathione peroxidase, while itself being oxidized to GSSG. GSSG is subsequently reduced back to GSH by glutathione reductase utilizing NADPH as a cofactor, thereby sustaining a high GSH/GSSG ratio and protecting cells from oxidative stress damage [58]. Beyond the redox cycle, GSH homeostasis also involves two mechanistically distinct enzymatic processes: 1) Extracellular GSH hydrolysis via GGT. GSH exported from the cell is hydrolyzed by GGT on the extracellular membrane surface, releasing glutamate, cystine, and glycine — constituent amino acids that can be reimported for intracellular GSH resynthesis. This GGT-mediated pathway thus constitutes a true degradation-and-recycling route that replenishes the amino acid precursor pool, including glutamate [62]. 2) Intracellular GSH conjugation via GST. Glutathione S-transferase (GST) catalyzes the conjugation of intracellular GSH with electrophilic compounds — both endogenous reactive metabolites and exogenous xenobiotics — forming glutathione conjugates (GS-X) that are exported via ABCC/MRP transporters [63]. Critically, this pathway does not hydrolyze GSH into its constituent amino acids and therefore does not replenish the glutamate pool or recycle GSH precursors. Rather, GST — in particular the glutathione S-transferase P (GSTP) isoform — function as central hubs in redox signaling, operating through two complementary mechanisms: (a) conjugation-dependent detoxification of electrophiles; and (b) catalysis of protein S-glutathionylation — the reversible addition of GSH to reactive protein cysteine residues that modulates protein structure and function in response to oxidative and nitrosative stress [64]. The pioneering work of Townsend, Tew and colleagues established that GSTπ acts as the primary forward catalyst of the S-glutathionylation cycle: by lowering the pKa of target cysteine residues, GSTπ facilitates thiolate formation and potentiates S-glutathionylation of specific protein clusters. Notably, GSTπ itself undergoes autoregulatory S-glutathionylation at Cys47 and Cys101, which disrupts its inhibitory interaction with c-Jun N-terminal kinase (JNK) and thereby licenses downstream stress response signaling [65,66]. The reverse reaction, deglutathionylation, is mediated by glutaredoxin (Grx), creating a cyclical conduit for redox-mediated signal transduction [67]. Extending this paradigm, GSTP has further been identified as an endoplasmic reticulum (ER)-resident protein that catalyzes S-glutathionylation of critical ER proteins — including PDI, BiP, calnexin, and SERCA — thereby influencing the unfolded protein response (UPR) and linking redox regulation to protein folding homeostasis [68].

2.4. Interconversion between glutamate and GSH

2.4.1. Glutamate as a precursor for GSH synthesis

As previously described, glutamate and cysteine are conjugated by GCL to form γ-glutamylcysteine, which is then combined with glycine by GS to synthesize GSH. The capacity for GSH synthesis from glutamate is dynamically regulated according to cellular demand: in the liver, exposure to hepatotoxic agents such as ethanol and certain drugs substantially increases GCL and GS activity, thereby enhancing GSH synthesis to support detoxification and redox protection [69]. Importantly, the regulatory mechanisms governing this process are highly context-dependent. In normal hepatocytes, stress-induced upregulation of GSH synthesis follows canonical adaptive pathways; however, in cancer cells, the Glu-GSH axis undergoes a fundamental reprogramming driven by oncogenic signaling, in which GSH biosynthetic capacity is constitutively elevated and the expression of GSH-related enzymes — including GSTP — is governed by altered transcriptional networks distinct from those operating in normal tissue [70]. Notably, studies in transgenic mouse models have demonstrated that deletion of major stress-response transcription factors does not uniformly suppress GSTP expression in vivo, and may paradoxically increase it in certain normal tissues, underscoring that the identity and relative contribution of transcriptional regulators of GSH synthesis shift substantially with cellular context [71,72]. These distinctions are of direct relevance to the disease-specific mechanisms discussed in later sections.

In the brain, neurons acquire glutamate primarily via the glutamate/GABA-glutamine cycle. During oxidative stress, this cycle is enhanced, directing glutamate preferentially into GSH synthesis rather than neurotransmitter pathways, thereby elevating neuronal GSH levels to counteract oxidative damage [73]. Astrocytes, which are rich in GS, facilitate the conversion of glutamate to GSH and release the dipeptide cysteinylglycine to neurons. This process establishes a “neuron-glia” collaborative antioxidant system, providing neurons with direct precursors for GSH synthesis and enhancing their overall antioxidant capacity [74].

2.4.2. GSH degradation and glutamate recycling

GSH can be degraded into simpler metabolites through specific enzymatic reactions. As detailed in Section 2.1, GGT-mediated hydrolysis of the γ-glutamyl bond initiates the extracellular γ-glutamyl cycle, ultimately recycling cysteine, glycine, and glutamate back into the cell for renewed GSH synthesis [75] Of note in the context of the Glu-GSH axis, GGT activity represents a quantitatively significant route by which glutamate is regenerated from exported GSH: GGT is predominantly expressed on the plasma membrane of hepatocytes, renal tubular cells, and intestinal epithelial cells, where this recycling mechanism maintains precursor availability for continuous GSH resynthesis [27].

This GGT-catalyzed degradation of GSH serves multiple functions: 1) It regulates intracellular GSH levels to maintain redox homeostasis. 2) It supplies glutamate, cysteine, and glycine that can enter other metabolic pathways, supplying essential amino acids. 3) It supports cellular detoxification by facilitating the elimination of exogenous and endogenous toxins. The synthesis and degradation of GSH constitute a dynamic equilibrium. By modulating GSH levels, cells maintain their redox status and protect against oxidative stress. It has been proposed — primarily in the context of neuronal brain metabolism — that GSH may act as a conditional buffer for glutamate homeostasis under specific pathological conditions when GSH turnover is accelerated [76]. The mechanistic basis for this hypothesis lies in the structure of the γ-glutamyl cycle: because GSH is one-third glutamate by composition and is present in neurons at millimolar concentrations with a relatively short half-life, pharmacological inhibition of enzymes that liberate glutamate from the cycle (GGT and OPLAH) reduces intracellular neuronal glutamate levels by 25–50% and suppresses miniature excitatory postsynaptic potential (mEPSC) frequency in primary cortical neurons, while inhibition of GSH biosynthesis has the opposite effect — elevating cytoplasmic glutamate and enhancing mEPSC frequency [52]. Notably, the glutathione cycle has also been shown capable of compensating for reductions in glia-derived glutamine when the glutamine-glutamate shuttle is pharmacologically disrupted, suggesting it may serve as a secondary reservoir that sustains synaptic glutamate supply under conditions of metabolic stress [52]. However, this remains a working hypothesis rather than an established mechanism in vivo. Classical metabolic evidence more robustly supports the direction of glutamate sustaining GSH synthesis, rather than the reverse; indeed, in neurons cysteine — not glutamate — is the rate-limiting substrate for GSH synthesis, and neuronal GSH levels are primarily governed by cysteine availability via the EAAC1 transporter rather than by intracellular glutamate supply [77]. The potential bidirectionality described above may be most relevant in brain tissue where tight control of extracellular glutamate is critical, particularly in neuropsychiatric conditions involving GSH deficits and glutamatergic dysregulation, and warrants further experimental investigation.

3. Regulatory signaling pathways governing the Glu-GSH axis

The signaling pathways regulating glutamate and GSH metabolism do not operate in isolation. Rather, they form an interconnected regulatory network in which multiple transcription factors converge on shared promoter elements, cross-regulate each other, and exhibit cell-type- and context-dependent interactions. The net effect of these pathways on GSH synthesis depends on the balance of activating signals and inhibitory signals (see Table 1). The cascade amplification mechanism — whereby excess glutamate triggers ROS generation, which depletes GSH and in turn impairs glutamate transporters — also constitutes a form of regulatory cross-talk between metabolism and signaling.

Table 1.

Summary of regulatory signaling pathways governing the Glu-GSH axis.

Pathway	Target element	Effect on GSH synthesis	Crosstalk with other pathways	References
Nrf2	ARE	↑ Promotes (GCLC, GS, SLC7A11)	Activated by low p53; suppressed by ATF3 (TGF-β); activates system X_c^-	[[78], [79], [80], [81], [82], [83]], [93], [96], [97]
AP-1	TRE	↑ Promotes (GCLC, GCLM)	Cooperates with Nrf2 (dual ARE + TRE sites); regulated by JNK	[[84], [85], [86], [87]]
NF-κB	ARE	↑ Promotes (GCLC, GCLM)	Cooperates with Nrf2 (normal cells); can act independently in cancer cells	[[88], [89], [90]]
System X_c^-	SLC7A11	↑ Promotes (supplies cysteine)	Upregulated by Nrf2; suppressed by ATF3; linked to extracellular glutamate levels	[[91], [92], [93]]
TGF-β/Samd	ATF3/ARE	↓ Suppresses (inhibits Nrf2)	Negatively regulates Nrf2; ATF3 is the effector	[[94], [95], [96]]
p53	Keap1/ARE	Bidirectional: low expression ↑, high expression ↓	Concentration-dependent modulation of Nrf2	[[97], [98], [99]]

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3.1. Cascade amplification between glutamate and GSH

The interactions between glutamate and GSH might be a vicious amplifying cycle [78]. An enhanced extracellular glutamate level due to excess release or reduced uptake, might cause overactivation of glutamate receptors on both neurons and astrocytes, and lead to elevated concentrations of intracellular calcium in these cells [79]. As a consequence, several calcium-dependent enzymes can be activated in a non-controlled manner and lead to cell death [80]. ROS, which are both byproducts and mediators of these enzymatic processes, subsequently deplete GSH [81]. Besides, ROS oxidize proteins such as the neuronal and glial glutamate transporters. This oxidation impairs glutamate reuptake, further promoting extracellular glutamate accumulation [82]. These events collectively reinforce a vicious cycle of excitotoxicity and oxidative damage.

3.2. Regulatory signaling pathways (Fig. 3)

3.2.1. The Nrf2 signaling pathway

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor governing the cellular antioxidant defense system. It regulates the expression of numerous antioxidant genes, including those involved in GSH synthesis, by binding to the antioxidant response element (ARE) in their promoter regions [83]. Under basal conditions, Kelch-like ECH-associated protein 1 (Keap1), an adaptor protein for the Cullin3-containing E3 ubiquitin ligase complex, binds to Nrf2 and targets it for ubiquitin-mediated proteasomal degradation, thereby suppressing antioxidant gene expression and sequestering Nrf2 in the cytoplasm [84]. Under oxidative stress, ROS modify specific cysteine residues on Keap1, inducing a conformational change that disrupts its ability to bind Nrf2 [85]. This stabilization allows Nrf2 to translocate into the nucleus, where it forms a heterodimer with small Maf proteins (sMaf) and binds to ARE [86]. This activation upregulates the expression of GSH synthesis-related genes, notably GCLC and GS, thereby enhancing GSH production [87]. The phosphatidylinositol 3-kinases/protein kinase B (PI3K/AKT) signaling pathway also facilitates Nrf2 nuclear translocation. Inhibition of PI3K/AKT signaling diminishes Nrf2 transcriptional activity, whereas overexpression of constitutively active AKT enhances it [88].

3.2.2. The AP-1 signaling pathway

Activating protein 1 (AP-1) is a heterodimeric transcription factor composed of Fos [89] and Jun [90]proteins, which binds to specific DNA sequences known as TPA response element (TRE). Multiple TRE binding sites are present in the promoter regions of both the human GCLC and GCLM genes. Studies have demonstrated that TRE elements participate in regulating both the basal and inducible expression of GCL genes [91]. Phosphorylation of c-Jun is essential for TRE-mediated GCL induction. Research has shown that inhibition of c-Jun N-terminal kinase (JNK) reduces c-Jun phosphorylation levels, subsequently blocking both GCL induction and the binding of c-Jun to TRE sites [92]. AP-1 and Nrf2 can cooperate under oxidative stress: both pathways are simultaneously activated, providing additive transcriptional upregulation of GCLC/GCLM, since the GCL promoter contains both TRE and ARE elements.

3.2.3. The NF-κB signaling pathway

Nuclear factor-kappa B (NF-κB) is a pivotal transcription factor involved in diverse biological processes including inflammatory responses, immune regulation, and cell survival. In its inactive state, NF-κB (most commonly as a p50/p65 heterodimer) is sequestered in the cytoplasm through interaction with its inhibitory protein, IΚβ. Under conditions of redox imbalance, elevated reactive oxygen species can activate upstream kinases such as TGF-β-activated kinase 1 (TAK1) or directly modify the IκB kinase (IKK) complex-composed of catalytic subunits IKKα and IKKβ, and the regulatory subunit IKKγ. Activation of the IKKβ subunit leads to phosphorylation of IΚβ, which triggers its ubiquitination and subsequent degradation by the proteasome. Degradation of IΚβ liberates NF-κB, allowing its translocation into the nucleus where it initiates transcription of downstream target genes, including GCLC and GCLM, thereby promoting GSH synthesis [93]. Conversely, reduced IKKβ expression suppresses NF-κB activation, diminishes its binding to GCLC/GCLM promoter regions, and consequently downregulates their expression [94]. Critically, the relationship between NF-κB and Nrf2 is context-dependent: in normal cells under acute oxidative stress, they cooperate to amplify antioxidant responses [95], in cancer cells with constitutive NF-κB activation, NF-κB can drive GSH synthesis independently of Nrf2, contributing to chemoresistance [93].

3.2.4. The glutamate/cystine antiporter system

The glutamate/cystine antiporter system (system X_c⁻), composed of a catalytic subunit SLC7A11 and a regulatory subunit SLC3A2, serves as a primary defense mechanism against oxidative stress. This antiporter facilitates the exchange of intracellular glutamate for extracellular cystine [96]. Upon entry, cystine is rapidly reduced to cysteine, which serves as a critical precursor for GSH synthesis [97]. Studies have demonstrated that activating transcription factor 3 (ATF3) suppresses SLC7A11 transcription by binding to its promoter, thereby limiting GSH synthesis [96]. Conversely, Nrf2, a key transcriptional regulator of the antioxidant response, enhances SLC7A11 expression by binding to ARE within its promoter, consequently promoting GSH synthesis [98].

3.2.5. The TGF-β/Smad signaling pathway

The canonical TGF-β/Smad signaling pathway typically activates gene transcription. However, under specific contexts, TGF-β exerts inhibitory effects. The core mechanism involves TGF-β receptor activation leading to Smad3 phosphorylation, which facilitates the formation and nuclear translocation of the Smad3/Smad4 complex. Instead of directly binding to gene promoters, this complex induces the expression of the transcriptional repressor ATF3. ATF3 then acts as the effector, binding directly to gene promoter regions and recruiting corepressor complexes to suppress gene transcription [99]. Based on this mechanism, studies have revealed that TGF-β1 activates the Smad3/Smad4 complex, upregulates ATF3 expression, and consequently attenuates Nrf2 signaling [100]. In GSH synthesis, TGF-β1 upregulation of ATF3 competitively binds to the ARE, inhibiting Nrf2 transcriptional activity. This results in reduced expression of the Nrf2 target gene GCL, diminished GSH synthesis, and ultimately lowered cellular antioxidant capacity with concomitant ROS accumulation. Notably, TGF-β1 does not affect Nrf2 protein levels per se in this process [101].

3.2.6. The p53 signaling pathway

The p53 gene has long been regarded as the guardian of the genome due to its dual role in both pro-oxidant and antioxidant functions. At relatively low expression levels, p53 induces its target gene p21, which competitively binds to Keap1. This interaction disrupts the Keap1-mediated ubiquitination and degradation of Nrf2, thereby stabilizing the Nrf2 protein, enhancing its nuclear translocation, and promoting the expression of cytoprotective genes to support cell survival [102]. In contrast, under conditions of high p53 expression, p53 directly interacts with Nrf2 to form a complex that impedes the binding of Nrf2 to the ARE. This mechanism suppresses the expression of antioxidant genes, including GCL, thereby attenuating the cellular antioxidant response [103]. This concentration-dependent switch in p53 function may be particularly relevant in the context of tumor suppression, where high p53 activity restrains the antioxidant capacity of cells undergoing oncogenic stress [104].

4. Dysregulation of the Glu-GSH axis in disease: common mechanisms and disease-specific features

Sections 4.1 4.2 juxtapose neuropsychiatric disorders and cancer to highlight a fundamental mechanistic contrast within the Glu-GSH axis. In the brain, Glu-GSH axis failure drives pathology through progressive GSH depletion, unchecked excitotoxicity, and neuroinflammatory amplification — a pattern of protective failure. In tumors, the same axis is actively co-opted and amplified: cancer cells constitutively elevate GSH biosynthesis to sustain proliferation, chemoresistance, and immune evasion — a pattern of pathological amplification.

4.1. Overview of neuropsychiatric disorders: a shared mechanistic logic (Fig. 4)

Across the spectrum of neuropsychiatric disorders — including neurodegenerative conditions (AD; PD; amyotrophic lateral sclerosis, ALS), acquired neurological disorders (epilepsy; ischemic stroke), and psychiatric illnesses (major depressive disorder, MDD; anxiety disorder; schizophrenia; bipolar disorder) — a convergent set of pathophysiological mechanisms links dysregulation of the Glu-GSH axis to disease onset and progression. This section organizes the evidence around four interlocking mechanistic nodes that are consistently engaged across diagnoses: 1) Glutamate excitotoxicity and calcium-driven ROS generation; 2) GSH depletion and failure of redox homeostasis; 3) Neuroinflammatory amplification; 4) Disruption of the glutamate transporter-GSH feedback loop. Individual disease contexts are introduced within each node to illustrate how common mechanisms manifest in disease-specific phenotypes. A summary of Glu-GSH alterations across conditions is provided in Table 2.

Table 2.

Glu-GSH axis alterations and mechanistic nodes in neuropsychiatric disorders.

Disorder	Glu alteration	GSH alteration	Key mechanistic features	Primary mechanisms
AD	↑ early; ↓ late	↓	GCLC deficit → Aβ/tau [105]; EAAT impairment [106]; ferroptosis [107]	1,2,3,4
PD	↑ early; ↓ late	↓	GPX4↓ → ferroptosis [108]; NLRP3 activation [109]	1,2,3
ALS	↑ (CSF)	↓	EAAT2↓ [110]; SOD1 mutation [111]; mitochondrial ROS [112]	1,2,3,4
Epilepsy	↑ (ictal)	↓	NMDA receptor [113]; GABA↓ [114]; Nrf2 suppression [115]	1,2,3,4
Ischemic stroke	↑ (acute)	↓	Dual EAAT/GCL energy failure [116]; ferroptosis [117,118]	1,2,3,4
MDD	↑ (PFC/hippocampus)	↓	EAAT2↓ [119,120]; HPA dysregulation [121]; BDNF↓ [122]	2,3,4
Anxiety disorder	Dysregulated	↓ or ↑	Amygdala GLO1 [123]; PFC-amygdala circuit [124]	2,3
Schizophrenia	NMDA hypofunction	↓ (PFC, CSF)	parvalbumin interneuron loss [125]; gamma oscillation deficit [126]	2,3,4
Bipolar disorder	↕ (state-dependent)	↓	GSH enzyme genes↓ hippocampus [127]; NAC responsive [128]	1,2,3

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4.1.1. Mechanism 1: Glutamate Excitotoxicity and Calcium-driven ROS generation

When glutamate release exceeds the clearance capacity of reuptake systems, it leads to sustained overactivation of ionotropic glutamate receptors, including N-methyl-d-aspartic acid (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. This overactivation results in massive calcium influx into neurons. The subsequent intracellular calcium overload triggers the activation of deleterious enzymes such as proteases, nucleases, and phospholipases, which induce mitochondrial dysfunction, oxidative stress, and ultimately culminating in neuronal damage and death [129]. Furthermore, glutamate receptor overstimulation and the accompanied calcium dyshomeostasis promote surplus ROS generation, which in turn depletes GSH reserves [130]. GSH maintaining cellular redox homeostasis by eliminating ROS and free radicals through the actions of enzymes such as glutathione peroxidase and GST. Additionally, GSH acts as a direct non-enzymatic antioxidant, reacting with free radicals and ROS without enzymatic catalysis. In neuropsychiatric disorders, decreased GSH induce oxidative stress. The resulting accumulation of ROS further inhibits the glutamate transporter EAAT2, impairing glutamate clearance from the synaptic cleft and thereby exacerbating excitotoxicity [78].

In the early stages of AD, significant disruption of the glutamate/GABA-glutamine cycle leads to progressive glutamate accumulation, resulting in excitotoxicity and neurotoxicity that ultimately trigger neuronal death [131]. Aberrant glutamate levels and dysfunctional NMDA receptors documented in AD brain tissue exacerbate excitotoxic damage [132]. Glutamatergic neurotransmission is severely impaired in AD, particularly within the hippocampus and cerebral cortex, contributing to memory dysfunction and cognitive deficits [133,134]. In PD, glutamatergic hyperactivity within basal ganglia circuitry contributes to dopaminergic neuron degeneration; the mechanisms have been extensively characterized in mouse models and human post-mortem tissue [135]. In ALS, chronic, progressive excitotoxicity mediated by overactivation of AMPA receptors triggers motor neuron degeneration and astrocytosis, ultimately leading to motor dysfunction and paralysis [136].

In ischemic stroke, ATP depletion from cerebral hypoperfusion disrupts Na⁺/K⁺-ATPase, causing cellular depolarization and massive glutamate release. The resultant calcium influx via NMDA receptors initiates a self-reinforcing excitotoxic-oxidative cascade [137,138]. In epilepsy, seizure-associated surges in extracellular glutamate produce both acute excitotoxic injury and chronic maladaptive remodeling of glutamate receptors and transporters that promotes epileptogenesis [139]. In psychiatric disorders, the excitotoxic threshold is lower, reflecting dysregulation of glutamatergic tone rather than acute glutamate flooding. In schizophrenia, NMDA receptor hypofunction paradoxically disinhibits glutamatergic output via interneuron loss, and pharmacological NMDA antagonists replicate schizophrenia-like phenotypes in healthy individuals [140]. In MDD, elevated glutamate in the prefrontal cortex (PFC) and hippocampus sustains NMDA receptor overactivation, downregulation of astrocytic EAAT2 expression impairs glutamate clearance from the synaptic cleft [119,120]. The calcium-derived ROS burst directly depletes GSH reserves [130], directly linking Mechanism 1 to Mechanism 2.

4.1.2. Mechanism 2: GSH depletion and failure of redox homeostasis

GSH is the principal low-molecular-weight antioxidant of the CNS, maintained at millimolar concentrations in neurons and astrocytes [141]. Its depletion — caused by excitotoxic ROS consumption, reduced biosynthetic precursor availability, or impaired GCL activity — is a convergent feature of virtually all major neuropsychiatric conditions. Because glutamate is the obligatory substrate for GCL-catalyzed GSH synthesis, conditions that dysregulate glutamate simultaneously compromise GSH production capacity.

Several converging mechanisms account for GSH depletion in neuropsychiatric contexts. 1) Excitotoxic calcium influx generates mitochondrial ROS that consume GSH faster than it can be resynthesized [9]. 2) Elevated extracellular glutamate inhibits the system X_c⁻, limiting cystine uptake and exacerbating GSH depletion [116]. 3) Energy failure reduces the ATP available for the two-step GCL/GS biosynthetic reaction [137]. 4) Neuroinflammatory cytokines directly suppress GCL expression and reduce neuronal GSH [142]. 5) Iron overload via the Fenton reaction consumes GSH and generates hydroxyl radicals while iron-calcium co-transport dysregulates calcium homeostasis, further amplifying NADPH oxidase-derived ROS [143].

In AD, in vivo Magnetic Resonance Spectroscopy (MRS) studies reveal reduced hippocampal GSH in AD patients relative to age-matched controls, accompanied by elevated intracellular pH [144]. The pH elevation likely reflects impaired mitochondrial oxidative phosphorylation and compensatory shifts in cellular buffering capacity secondary to GSH-dependent redox failure, rather than representing an independent pathological driver. Post-mortem analyses further confirm decreased cerebral GSH concurrent with elevated iron levels in AD patients compared to age-matched healthy elderly individuals [107]. The co-occurrence of GSH depletion and iron accumulation is mechanistically significant: under conditions of GSH deficiency, glutathione peroxidase 4 (GPX4) activity is compromised, impairing the enzymatic reduction of phospholipid hydroperoxides. Concurrently, elevated labile iron catalyzes the Fenton reaction (Fe²⁺ + H₂O₂ → Fe³⁺ + ·OH), generating hydroxyl radicals that initiate lipid peroxidation chain reactions. Together, these converging conditions including GSH depletion, GPX4 inactivation, and iron overload, fulfil the mechanistic criteria for ferroptosis, an iron-dependent, lipid peroxidation-driven form of regulated cell death increasingly recognized as a contributor to neuronal loss in AD [104]. Mechanistically, GCLC deficiency elevates the Aβ42/40 ratio and promotes tau aggregation via disulfide bond formation, directly linking GSH depletion to amyloid and tau pathology [105]. In PD, GSH depletion in the substantia nigra was reported as early as 1994 [145], and dopamine-induced ubiquitination and loss of GPX4 activity have since been shown to trigger ferroptosis of dopaminergic neurons [108]. In ALS, elevated ROS and decreased GSH in the CNS of ALS patients are well documented [112], and Cu/Zn superoxide dismutase (SOD1), an antioxidant enzyme that protects cells from superoxide radicals, is frequently mutated in familial ALS [146]. SOD1 mutations enhance oxidative stress and reduce GSH levels, further compromising cellular antioxidant capacity and increasing vulnerability to oxidative damage. Similarly, SOD1 mutations can induce mitochondrial dysfunction, leading to excessive ROS production [111], thereby establishing a vicious redox cycle.

In psychiatric conditions, GSH deficits are measurable in vivo. MRS studies of drug-free schizophrenia patients demonstrate approximately 52% lower GSH in the medial PFC relative to healthy controls, with a further 27% reduction in cerebrospinal fluid (CSF) [126]. Post-mortem caudate nucleus from schizophrenia patients shows significantly reduced GSH levels [147]. In MDD, reduced GSH levels in plasma and erythrocytes are consistently reported in untreated patients, and antidepressant treatment partially restores GSH-related enzyme activities [148]. In bipolar disorder, downregulation of GSH synthetase, glutathione peroxidase, and GGT genes in the hippocampus correlates with reduced GSH and elevated oxidative stress markers [127]. In anxiety disorder, pharmacological depletion of GSH in the amygdala and hippocampus in rodents exacerbates anxiety-like behaviors, while GLO1 overexpression in the cingulate cortex correlates with heightened anxiety [123].

4.1.3. Mechanism 3: neuroinflammatory amplification

Neuroinflammation represents a mechanistic bridge between the initial excitotoxic-redox insult and the chronic pathological remodeling characteristic of most neuropsychiatric disorders. GSH depletion and ROS accumulation activate pattern-recognition receptors on microglia, triggering the NLRP3 inflammasome and NF-κB signaling, with consequent release of IL-1β, TNF-α, and IL-6 [113]. These pro-inflammatory mediators directly damage neurons and also: 1) Upregulate glutamate release from astrocytes; 2) Downregulate astrocytic EAAT2 expression, impairing glutamate clearance; and 3) Suppress GCL activity, further reducing GSH biosynthesis [119]. The result is a feed-forward loop in which neuroinflammation amplifies both glutamate excitotoxicity and GSH deficit simultaneously.

In AD, activated microglia and astrocytes in the vicinity of amyloid plaques release IL-1β and TNF-α that further suppress EAAT-mediated glutamate clearance [106] and reduce neuronal GSH [149], synergizing with excitotoxic insults. In PD, neuroinflammation in the substantia nigra accompanies dopaminergic neuron loss [135], α-synuclein aggregates activate microglial NLRP3 [109], and GSH depletion amplifies this inflammatory cycle [150]. In ALS, reactive astrogliosis driven by SOD1 mutant toxicity produces a neuroinflammatory environment that amplifies motor neuron excitotoxic vulnerability [151]. In epilepsy, IL-1β released from activated microglia after GSH depletion directly enhances NMDA receptor conductance and promotes chronic epileptogenesis [113]. In MDD and anxiety disorders, elevated peripheral inflammatory markers (CRP, IL-6, TNF-α) converge on the same central neuroinflammatory mechanisms [[152], [153], [154]].

4.1.4. Mechanism 4: the glutamate Transporter-GSH feedback loop

A critical mechanistic node integrating the preceding mechanisms is the bidirectional regulation between astrocytic glutamate transporters, principally EAAT2 and the GSH redox system. EAAT2 is the predominant transporter responsible for clearing approximately 90% of synaptic glutamate, its functional integrity is exquisitely sensitive to the cellular redox state [78].

ROS-mediated oxidation of EAAT2 cysteine residues directly impairs transporter function, reducing glutamate uptake velocity. The consequent rise in extracellular glutamate elevates system X_c⁻ mediated glutamate efflux that simultaneously limits cystine import and further depresses GSH synthesis [116]. Conversely, GSH depletion removes the redox buffer that protects EAAT2 from oxidative inactivation, creating a positive-feedback loop: GSH deficit → EAAT2 oxidation → reduced glutamate clearance → elevated extracellular glutamate → NMDA overactivation → ROS generation → further GSH depletion [78].

This transporter-GSH loop has been documented in multiple disease. In MDD, downregulation of astrocytic EAAT2 expression impairs glutamate clearance from the synaptic cleft, GSH depletion further compromises residual transporter activity, producing the sustained synaptic glutamate elevation and NMDA overactivation documented in MDD brain [119]. In ALS, EAAT2 protein and transcript levels are markedly reduced in affected motor cortex and spinal cord, at least partly attributable to oxidative damage driven by SOD1-related GSH insufficiency [110]. In ischemic stroke, energy failure simultaneously prevents glutamate re-uptake and depletes GSH, collapsing both protective mechanisms simultaneously [116]. In schizophrenia, the GSH deficit observed in the medial PFC is correlated with gamma-band oscillatory abnormalities consistent with reduced GABAergic inhibition secondary to impaired glutamate clearance [126]. An important developmental dimension of this loop is relevant to schizophrenia: prenatal or early postnatal GSH deficits during critical windows of glutamatergic circuit maturation impair parvalbumin interneurons development, producing lasting alterations in NMDA receptor subunit composition and EAAT expression that persist into adulthood [125]. This may explain why antioxidant interventions show greater efficacy in early illness stages [155].

4.1.5. Therapeutic implications of the mechanistic framework

Reframing neuropsychiatric Glu-GSH dysregulation around shared mechanisms reveals convergent therapeutic targets. Several intervention strategies address multiple mechanistic nodes simultaneously:

N-acetylcysteine (NAC) replenishes cysteine substrate for GCL (Mechanism 2) and thereby restores glutamate-cystine exchange stoichiometry (Mechanisms 2 and 4), clinical evidence supports its efficacy in schizophrenia [156,157] and bipolar depressive phases [128,158]. Nrf2 activators transcriptionally upregulate both GCL subunits and EAAT2 (Mechanisms 2 and 4), preclinical evidence spans AD [159], PD [160], stroke [161], and epilepsy models [162]. NMDA receptor modulators target Mechanism 1, their benefits in AD [163], MDD [164], and ALS [165] are consistent with a shared excitotoxic substrate. Anti-ferroptotic strategies targeting GPX4 stabilization are particularly relevant for PD [108], stroke [117,118], and ALS [166], where the GSH depletion-ferroptosis axis is well defined.

The stage and trajectory of disease determines which mechanism predominates and therefore which intervention is optimal. In acute ischemic stroke, Mechanisms 1 and 2 occur quasi-simultaneously within minutes; acute NMDA-blocking and antioxidant strategies have the narrowest therapeutic window. In chronic neurodegenerative diseases, all four mechanisms operate in parallel, justifying combination approaches. In psychiatric disorders, the predominant nodes (Mechanisms 1-4) respond to both GSH-targeted and glutamate-targeted interventions on slower timescales that permit maintenance strategies.

4.2. Overview of cancer: a shared mechanistic logic (Fig. 5)

Unlike the neuropsychiatric disorders, in which Glu-GSH dysregulation primarily reflects a failure of homeostatic defense, cancer cells actively co-opt and amplify the Glu-GSH axis as a pro-survival resource: constitutively elevated GSH biosynthesis, driven by reprogrammed glutamine catabolism and context-dependent transcriptional rewiring, simultaneously fuels proliferation, shields cells from oxidative stress, amplifies mitogenic signaling, and remodels the tumor immune microenvironment. This section organizes the evidence around six interlocking oncogenic roles that are recurrently engaged across tumor types: 1) Promotion of tumor cell proliferation through glutamate-derived biosynthetic and redox support; 2) Reprogramming of tumor metabolism via integration of the Glu-GSH Axis with TCA cycle anaplerosis and the NADPH system; 3) Regulation of antioxidant defense that enables survival under the elevated ROS burden of malignant metabolism; 4) Modulation of tumor cell signaling through glutamate receptor-coupled activation of MAPK/PI3K-Akt-mTOR-Nrf2; 5) Mediation of drug resistance through GSH-dependent ROS neutralization and GS-X conjugate export; and 6) Facilitation of immune evasion through GSH-driven remodeling of the immunosuppressive tumor microenvironment.

4.2.1. Promoting tumor cell proliferation

Glutamate, a key intermediate in glutamine metabolism, provides carbon skeletons and nitrogen sources necessary for the synthesis of macromolecules, thereby supporting the rapid proliferation of tumor cells [167]. Dysregulation of the Glu-GSH balance can lead to metabolic disturbances and exacerbated oxidative stress in tumor cells. On one hand, aberrant glutamate metabolism can enhance GSH synthesis, augmenting the antioxidant capacity of tumor cells and promoting their proliferation and survival. On the other hand, elevated GSH levels can further influence glutamate metabolism, creating a vicious cycle that drives tumor initiation and progression. Studies have shown that non-small cell lung cancer cells rely on glutamine-derived glutamate for GSH synthesis, disruption of this pathway significantly suppresses cell proliferation and enhances radiosensitivity [168]. GSH can also activate the mTOR signaling pathway, which links obesity to breast cancer. Through metabolomic profiling of tumor microenvironment metabolites and comparative in vivo/vitro experimentsin normal-diet and high-fat-diet groups, researchers confirmed that elevated GSH levels in the tumor interstitial fluid of obese mouse model promoted breast cancer cell invasion and proliferation. Treatment with the GSH synthesis inhibitor buthionine sulfoximine (BSO) significantly suppressed mammary tumor growth [169].

4.2.2. Reprogramming tumor metabolism

Tumor cells undergo substantial metabolic reprogramming to sustain hallmark malignant phenotypes, including uncontrolled proliferation and metastatic dissemination. As cellular metabolism is reprogrammed, glutamate metabolic pathways are concomitantly modified. Tumor cells hydrolyze glutamine to glutamate via GLS, driving GSH synthesis to sustain mitochondrial function and replenish the TCA cycle intermediates. Inhibition of this pathway induces a metabolic crisis in tumor cells-characterized by TCA cycle suppression and ROS surge, confirming the Glu-GSH axis as a central node in metabolic reprogramming [170]. GDH1 sustains GSH production from glutamate, maintaining NADPH and GSH levels, suppressing ROS accumulation, and promoting tumor growth. Inhibiting GDH1 or blocking the Glu-GSH axis can shift tumor metabolism from an “antioxidant-proliferative” state to a “ROS-pro-apoptotic” state [171]. In osteosarcoma, for example, tumor cells rely on liver-type glutaminase rather than direct TCA cycle-derived α-KG to recruit and activate mTORC1 on lysosomal surfaces, thereby inhibiting autophagy and promoting cell growth [172].

GSH synthesis is closely linked to glutamine metabolism. Glutamate derived from glutamine metabolism serves as a precursor for GSH synthesis, providing both antioxidant defense and metabolic support for tumor cells. For instance, studies show that glutamate produced by GLS1-catalyzed glutamine metabolism is preferentially directed toward GSH synthesis rather than entering the TCA cycle or nucleotide synthesis. Mutations in glutathione synthetase are associated with recurrence in bladder cancer and small cell lung cancer, indicating that the Glu-GSH axis directly influences tumor progression [173]. Metabolomic sequencing of clear cell renal cell carcinoma revealed large-scale remodeling of the metabolic network during tumor progression and increasing invasiveness, with activation of GSH metabolic pathway closely correlating with proliferative and invasive phenotypes [174]. By integrating glutamine metabolism, TCA cycle anaplerosis, and the NADPH/GSH antioxidant system, the Glu-GSH axis constitutes a core regulatory axis in tumor metabolic reprogramming, determining if tumor cell survival or death under oxidative stress.

4.2.3. Regulating antioxidant defense

GSH serves as an essential intracellular antioxidant, responsible for shielding tumor cells from oxidative stress damage [175]. Tumor cells commonly exhibit elevated GSH levels to offset the substantial ROS burden arising from metabolic reprogramming and mitochondrial dysfunction, a mechanism that supports their survival and proliferative capacity [176,177]. Studies have demonstrated that IFN-γ inhibits extracellular glutamate uptake through activation of the JAK-STAT signaling pathway. This disruption of intracellular glutamate availability impedes GSH synthesis, leading to ROS accumulation and subsequent induction of ferroptosis in tumor cells. This process is accompanied by a marked increase in tumor immunogenicity, which depends on the presence of tumor-infiltrating CD8⁺ T cells. [178]. Furthermore, the enzyme GCLC also contribute to the antioxidant defense mediated by GSH in tumors. Recent research has shown that the NOP2/Sun RNA methyltransferase 2 (NSUN2) enhances m5C modification and mRNA stability of GCLC via lactylation, thereby boosting GSH production, reducing lipid peroxidation, and suppressing ferroptosis [179].

4.2.4. Modulating tumor cell signaling

Glutamate additionally functions as a signaling molecule in tumor cells, participating in the regulation of multiple signaling pathways. Published studies across a range of malignancies — gastric cancer, melanoma, glioma, and breast cancer — have demonstrated that glutamate, acting through NMDA and metabotropic glutamate (mGlu) receptors, activates the MAPK/PI3K-Akt-mTOR pathway. This activation induces phosphorylation of transcription factor Nrf2, which in turn up-regulates GSH expression, modulates the Bcl-2/Bax balance, inhibits mitochondrial apoptosis, and thereby promotes cell proliferation. For example, in human gastric cancer MKN45 cells, which express the NMDA receptor subunit NR2A, glutamate stimulation significantly enhances proliferation-an effect that is abrogated by NMDA receptor antagonists [180]. In human melanoma cells, glutamate-mediated activation of mGluR1 triggers phosphorylation of ERK1/2 and PI3K/Akt, driving proliferative signaling [181]. Persistently active mTORC1 suppresses SIRT4, relieving its inhibition of GLS and thereby enhancing glutamine uptake and glutamate production. The resulting glutamate is primarily utilized for GSH synthesis, maintaining high intracellular GSH levels to support rapid cell proliferation [182]. Conversely, in glioma cells, inhibiting mGluR1 disrupts the PI3K/Akt/mTOR cascade and significantly suppresses proliferation [183]. In breast cancer cells, mGluR1 activation of the PI3K/Akt pathway upregulates Nrf2 transcription, subsequently increasing GCL and GSH synthesis, thereby enhancing the antioxidant capacity of tumor cells [176]. The Bcl-2/Bax pathway acts as a molecular switch for mitochondrial apoptosis. Elevated GSH helps sustain the anti-apoptotic activity of Bcl-2, prevents Bax translocation, inhibits loss of mitochondrial membrane potential, and ultimately block the mitochondrial apoptotic pathway [184].

4.2.5. Mediating tumor drug resistance

Dysregulation of the Glu-GSH axis can significantly affect tumor cell sensitivity to chemotherapeutic agents. Many chemotherapeutic drugs exert their cytotoxic effects through ROS generation, however, GSH can neutralize ROS, thereby diminishing treatment efficacy. One investigation into cisplatin resistance in lung cancer has revealed that cell survival after cisplatin exposure inversely correlates with the extent of DNA damage. Intracellular GSH, in concert with active DNA repair pathways, substantially reduces cisplatin-induced DNA damage and promotes lung cancer cell survival. Furthermore, Nrf2 hyperactivation also contributes to chemoresistance in lung cancer cells [185]. Multidrug resistance-associated proteins (MRPs), which widely expressed GSH transporters in human tissues, are implicated in this process. Studies show that drug-resistant ovarian cancer cells simultaneously exhibit high expression of GCLC and MRP. Elevated GSH levels in these cells promote tumor cell resistance to agents such as doxorubicin and vincristine [186]. In sorafenib-resistant hepatocellular carcinoma cells, upregulated peroxisome proliferator-activated receptor delta (PPARδ) enhances glutamine metabolism, characterized by increased production of reducing equivalents — including NADPH and GSH — from glutamine, together with elevated glutamine-derived lipid synthesis. These adaptations collectively bolster the antioxidant capacity of resistant cells [187]. Additional research indicates that glutamine promotes GSH synthesis and facilitates cancer stem cell formation via the β-catenin pathway, further influencing drug resistance [188]. Conversely, targeting glutamine metabolism can restore chemosensitivity. The novel SLC1A5 inhibitor V-9302 increases the sensitivity of hepatocellular carcinoma cells to CB-839. Combined treatment with CB-839 and V-9302 depletes GSH, induces ROS accumulation, and leads to cancer cell apoptosis [189].

4.2.6. Facilitating immune evasion

A multi-omics analysis in lung cancer revealed that tumors with heightened GSH metabolism exhibit suppression of the mTOR–IFN–γ axis in CD8⁺ T cells, leading to T cell exhaustion. Elevated GSH levels also contribute to lactate accumulation, which in turn promotes M2 macrophage polarization and upregulates PD-L1 expression, collectively fostering an immunosuppressive “cold tumor” microenvironment [190]. Converting the tumor microenvironment from “cold” to “hot” can significantly enhance cytotoxic T cell infiltration and efficiency. Zhao et al. developed a carrier-free self-assembled nanoparticle, BVC, based on an ASCT2 (encoded by SLC1A5) inhibitor combined with a PD-1/PD-L1 blocker. This system blocks glutamine/glutamate uptake, depletes GSH, induces ROS and endoplasmic reticulum stress (ERS), upregulates Fas and PD-L1 on tumor cells. These changes collectively enhance CD8⁺ T cell recognition while attenuating immune evasion [191]. In breast cancer, cancer-associated fibroblast (CAF) with enhanced autophagy secretes large amounts of glutamine. Tumor cells take up this glutamine, convert it to glutamate via GLS, and synthesize GSH, thereby protecting themselves from ROS damage while simultaneously suppressing adjacent T cell activity, promoting both chemoresistance and immune escape [192]. Single-cell metabolic flux analysis (scFEA) in colorectal cancer further revealed that it is the Glu-to-GSH metabolic step, downstream of GLS, rather than Glu-to-α-KG flux, that predominantly governs T cell cytotoxicity, pharmacological inhibition of GCLC elevated immunoproteasome activity, enhanced MHC-I-mediated tumor antigen presentation, and sensitized colorectal tumors to anti-PD-1 therapy [193]. Beyond these tumor-intrinsic mechanisms, the immune system serves as a critical intermediary in the broader cancer-nervous system crosstalk: neural signaling modulates the tumor immune microenvironment through neurotransmitter-receptor interactions on immune cells, while tumor-derived inflammatory factors reciprocally alter neural activity and promote neuronal hyperexcitability [194,195]. This neuro-immune-tumor triad further underscores the integrative role of the Glu-GSH axis at the intersection of neuropsychiatric and oncological pathophysiology, reinforcing the rationale for the dual-domain framework adopted in this review.

5. Non-invasive detection of glutamate and GSH: MRS techniques and clinical translation

The clinical translation of the mechanistic knowledge reviewed in Sections 2 3 4 requires non-invasive biomarker tools capable of monitoring glutamate and GSH dynamically in living subjects. As discussed, changes in the Glu-GSH axis — including elevated synaptic glutamate, reduced brain GSH, and shifts in the Glu/GSH ratio — may precede overt clinical symptoms in neurodegenerative and psychiatric disorders, and the direction of these changes (GSH depletion vs. compensatory GSH elevation) varies by disease and stage. Traditional detection methods for glutamate and GSH, such as liquid chromatography and mass spectrometry, necessitate invasive tissue or fluid sampling. MRS currently provides the non-invasive method for quantifying these metabolites in the living human brain, making it uniquely suited for translational research bridging the mechanistic insights of this review to clinical application.

5.1. Advantages of MRI technique in clinical diagnosis

Magnetic Resonance Imaging (MRI) is a non-invasive imaging technique. It is characterized with a strong magnetic field and radiofrequency pulses to excite ¹H, ³¹P, ²³Na and ¹³C within the tissues then generates images by detecting the emitted energy signals. This approach causes no direct physical injury to patients and avoids risks such as infection or bleeding [196]. MRI can generate multi-planar and multi-angular images, including axial, sagittal, and coronal views [197]. Moreover, MRI excels in soft tissue imaging, offering high contrast and resolution superior to conventional CT [198]. Beyond anatomical visualization, MRI technique can dynamically assess the function of tissues and organs, a branch known as functional magnetic resonance imaging (fMRI). The core techniques of fMRI primarily include diffusion-weighted imaging (DWI) [199,200], Perfusion-weighted imaging (PWI) [201], Blood-oxygen-level-dependent functional MRI (BOLD-fMRI) [202,203], etc. By utilizing a series of advanced imaging sequences and analytical methods, fMRI accurately detects dynamic changes at the microscopic level, providing a basis for disease diagnosis and treatment.

5.2. Detection of glutamate and GSH using MRS

MRI has emerged as a vital tool for studying cerebral systemic metabolism due to its non-invasive nature, high tissue resolution, and multi-modal imaging capabilities.

MRS is a non-invasive MRI technique that detects metabolites based on differences in their resonance frequencies, known as chemical shifts, arising from variations in the local magnetic environment of ¹H. This allows for the in vivo, non-invasive monitoring of dynamic changes in multiple metabolites, proving highly valuable for assessing metabolic alterations in living organisms [204]. The non-invasive detection of glutamate and GSH facilitates early disease diagnosis, treatment monitoring, and prognostic evaluation.

5.2.1. Conventional MRS (PRESS)

The quantification of glutamate and GSH by conventional MRS (PRESS) primarily relies on the specific chemical shift signals generated by these compounds within a magnetic field [205]. When an external magnetic field is applied, differences in the local magnetic environment surrounding different ¹H cause slight variations in their resonance frequencies, known as chemical shifts. Several clinically important observations have emerged from PRESS studies relevant to the disease mechanisms described in Section 4. A study utilizing PRESS to measure glutamate levels in 35 patients with medulloblastoma identified glutamate as a strong predictor of survival, with its concentration in tumor tissue significantly correlating with patient survival rates [206], it directly reflecting the metabolic reprogramming of the Glu-GSH axis discussed in Section 4.2.2. Early response to antipsychotic treatment is one of the most critical factors influencing long-term symptoms and functional outcomes in psychotic disorders. Glutamate and GSH have emerged as potential therapeutic targets for patients who respond poorly to dopamine-blocking antipsychotics. A study using 7.0-T MRI to assess glutamate and GSH levels in the dorsal anterior cingulate cortex of 26 first-episode psychosis patients and 27 healthy controls found that higher GSH levels were significantly associated with a shorter treatment response time, suggesting that elevated GSH may indicate a more favorable prognosis. Conversely, higher glutamate levels were linked to more severe functional impairment. Therefore, interventions aimed at increasing brain GSH levels may potentially improve treatment outcomes in early psychosis [207]. These findings echo the Mechanism 1 (glutamate excitotoxicity) and Mechanism 2 (GSH depletion) framework in Section 4.1: GSH preservation at early disease stages may reflect residual antioxidant capacity, whereas elevated glutamate signals the excitotoxic burden.

5.2.2. MEGA-PRESS: enhanced specificity and original data

Although PRESS has been demonstrated to detect GSH, its clinical application faces challenges due to the low cerebral concentration of GSH (1.5-3 mM), suboptimal signal-to-noise ratio in cerebral spectra, and significant spectral overlap between metabolite peaks of varying intensities (creatine, glutamate, glutamine, etc.) [208].

Mescher-Garwood Point Resolved Spectroscopy (MEGA-PRESS) is a J-difference editing technique that enhances detection sensitivity and specificity by selectively exciting the target proton signals of specific metabolites while suppressing background signals [209]. This method achieves selective editing by targeting the Cys-β-CH₂ proton of cerebral GSH, which resonates at a chemical shift of approximately 2.95 ppm [210]. The use of MEGA-PRESS for non-invasive detection of human brain GSH can address the issues of signal overlap between GSH and other metabolites, as well as the difficulty in accurate quantification with conventional PRESS. This strategy involves acquiring GSH-edited spectra using J-difference editing to obtain difference spectra containing primarily GSH and partially co-edited metabolites. These difference spectra are then directly input into post-processing software (LC-Model and others) for fitting using a pre-calculated basis set. Finally, absolute concentrations are derived using the water signal as an internal reference. This approach validates that the combined “difference-editing” and post-processing enables in vivo, non-invasive, and absolute quantification of human brain GSH, providing a reliable and reproducible measurement method for clinical research on neurodegenerative diseases, psychiatric disorders, and oxidative stress-related mechanisms [211]. A recent study utilizing this technique assessed changes in the antioxidant system in patients with vascular mild cognitive impairment (vMCI). The results indicated that, compared to cognitively normal coronary heart disease (CHD) controls, vMCI patients exhibited higher GSH levels in the anterior cingulate cortex, while no significant difference was observed in the occipital cortex. Furthermore, elevated GSH levels in the anterior cingulate cortex were negatively correlated with executive function performance. This suggests that increased GSH may represent a compensatory response to oxidative stress, yet this compensation might be associated with cognitive decline. Notably, these findings contrast with the trend of decreased GSH levels observed in AD patients, indicating that mild cognitive impairments of different etiologies may involve distinct oxidative stress mechanisms [212]. In MDD, a MEGA-PRESS study combining MRS and resting-state fMRI in 28 MDD patients and 30 healthy controls found significantly lower GSH in the medial PFC and precuneus in MDD. Critically, in healthy controls, GSH and glutamate levels were positively correlated within both regions — a relationship that was absent in MDD patients [213]. This decoupling of the Glu-GSH relationship provides direct in vivo imaging evidence for the Mechanism 4 feedback loop (Section 4.1.4): disruption of the coordinated GSH-EAAT2 axis in MDD, where GSH depletion impairs the redox protection of glutamate transporters, unravelling the physiological Glu-GSH coupling.

Based on this technique, we selected the thalamus of a healthy volunteer and a patient with aura migraine as the voxel locations, aiming to include as much cortical area as possible within each voxel while avoiding interference from skull impurities (Fig. 6a). The data presented in Fig. 6 are original, unpublished data acquired by our group. All MRS data were acquired using 3.0-T MR scanner (Discovery MR750w, GE Healthcare, Milwaukee, WI, United States) with a 24-channel head coil. In the MEGA-PRESS sequence, a 20 ms Gaussian 180° radiofrequency pulse served as the editing pulse, applied before and after the second 180° slice-selective radiofrequency pulse. The editing pulse was applied at 7 ppm in the Edit-OFF scan and at 4.56 ppm—coupled to the GSH spin resonance at 2.95 ppm—in the Edit-ON scan. When both scans were in the Edit-OFF state, the GSH signal at 2.95 ppm remained largely unaffected, similar to conventional MRS sequences. The acquired spectra primarily consisted of signals from all non-edited metabolites (Glu, NAA, Cr, etc.), making the GSH signal difficult to distinguish (Fig. 6b). To obtain the GSH-edited difference spectra, the Edit-ON and Edit-OFF spectra were aligned by minimizing difference signals at 2.01 ppm for N-acetyl-aspartate, 3.21 ppm for choline, and 3.03 ppm for creatine (Fig. 6c). Spectral fitting was performed using LC-Model software with an internal basis set to evaluate metabolite levels in the Edit-OFF spectra and the GSH-edited difference spectra. Metabolite signal intensities were normalized to the unsuppressed water signal within the voxel. Based on previous studies [214], the mean total creatine concentration was set at 8 mM to calculate metabolite concentrations for glutamate and GSH (Fig. 6d). The results showed glutamate concentrations of 7.2 mM and GSH concentrations of 2.1 mM in the healthy volunteer, while in the aura migraine patient, glutamate concentration was 7.1 mM and GSH concentration was 1.6 mM. The successful application of this technique will provide a method on the changes of Glu-GSH axis in diseases.

Fig. 6 — Detection of Glutamate and GSH in the thalamus using MEGA-PRESS. (Original, unpublished data from our group.) (a) Example voxel placement for MRS in the thalamus. (b) Metabolite signal peaks acquired in the Edit-OFF state, with the light blue line representing spectra, the red line representing fit, and the black line representing residual. (c) GSH-edited difference spectra obtained after spectral alignment and differential processing, with the light blue line representing spectra, the red line representing fit, the black line representing residual, and the dark blue line representing pure GSH signal. (d) Statistical plot of metabolite concentrations in the thalamus of a volunteer and an aura migraine. GSH: glutathione; Glu: glutamate; Gln: glutamine; GABA: γ-aminobutyric acid; ml: myo-inositol; tCr: total creatine; tCho: total choline; NAA: N-acetyl-aspartate; NAAG: N-acetyl-aspartyl-glutamate; tNAA: total NAA (NAA + NAAG).

5.2.3. Other MRS sequences: STEAM, semi-LASER, SPECIAL

Besides MEGA-PRESS, there are other sequences in MRS capable of detecting glutamate and GSH. A recent study utilizing stimulated echo acquisition mode (STEAM) sequence on 7.0-T MRI to perform spectrum scans on 81 first-episode psychosis patients and 91 volunteers, compared with volunteers, patients had lower levels of glutamate and GSH in the anterior cingulate and lower level of GSH in the thalamus. [215]. The hippocampus is a challenging region to detect using conventional MRS, a study employed a semi-LASER sequence on a 3.0-T MRI, using a relatively small voxel covering approximately 62% of the hippocampal volume to quantify metabolites such as glutamate, GSH, and creatine, etc. [216]. The amygdala plays a key role in emotional learning and processing. The spin echo full intensity acquired localized (SPECIAL) sequence, together with a transmit/receive coil, was used to perform very short-TE MRS at 3.0-T to determine the neurochemical profile in a voxel containing the amygdala in 21 volunteers, the concentration of total N-acetylaspartate (NAA), creatine, glutamate and GSH were quantified [217].

5.2.4. Multi-metabolite editing: the HERMES sequence

Building upon conventional MRS techniques, the HERMES sequence enables the simultaneous editing of multiple metabolites, including GABA, glutamate, and GSH, within a single scan. The shortened total acquisition window reduces phase errors accumulated due to subject motion [218]. The neonatal period represents the most rapid phase of brain development, and accurate measurement of these metabolites is crucial for understanding normal development and mechanisms of brain injury. The HERMES sequence has successfully detected GABA, glutamate, glutamine and GSH in the neonatal brain, achieving spectra with sufficient signal-to-noise ratio and spectral resolution to allow reliable fitting and quantification of these low-concentration metabolites [219]. Concurrently, the HERMES sequence has been applied to detect cerebral metabolites in patients with traumatic brain injury (TBI). Studies have found significantly higher levels of GABA, glutamate and glutamine in mild TBI patients compared to controls, while GSH levels showed no significant difference, providing important insights into the biochemical alterations following TBI [220].

6. Conclusion and future perspectives

Glutamate and GSH play crucial roles in human physiological and pathological processes. The metabolic interplay between glutamate and GSH — mediated through the γ-glutamyl cycle, system X_c⁻, and a network of converging transcriptional regulators including Nrf2, AP-1, NF-κB, TGF-β/Smad, and p53 — constitutes a central axis in cellular redox homeostasis. Disruption of this interplay underlies the pathogenesis of neurological disorders [221], psychiatric disorders [222] and cancer [223] through shared mechanisms of excitotoxicity, oxidative stress, transporter dysfunction, and ferroptosis. Critically, examining the Glu-GSH axis across both protective failure in neuropsychiatric disorders and pathological amplification in cancer reveals mechanistic connections and therapeutic paradoxes that would remain invisible in a single-domain analysis. The emerging field of Cancer Neuroscience has established that neurons and tumors engage in bidirectional glutamatergic communication [[34], [35], [36], [37]], and epidemiological evidence links psychiatric morbidity to increased cancer risk [38]. At the molecular level, the directional contrast — GSH depletion driving neurodegeneration versus GSH elevation sustaining tumor survival — gives rise to a critical therapeutic paradox: GSH restoration benefits the injured brain but may inadvertently support tumor antioxidant defense, while GSH depletion strategies in oncology risk exacerbating neurotoxicity. Only by appreciating the full spectrum of Glu-GSH axis dysregulation — from neurodegeneration to oncogenesis — can the therapeutic landscape and its inherent paradoxes be adequately navigated. Therefore, this review introduces the integrative framework of the Glu-GSH axis, providing a new perspective on disease pathogenesis.

Furthermore, alterations in the Glu-GSH axis may affect diseases in other organ systems. In the liver, deficiency of GCL can block the synthesis of GSH from glutamate, thereby alleviating lipid abundance by modulating the Nrf2 pathway [224]. Elevated vascular calcium levels inhibit the cystine-glutamate antiporter and GPX4 activity, reducing GSH synthesis and inducing ferroptosis in vascular smooth muscle cells, which contributes to vascular calcification in chronic kidney disease [225]. Additionally, the Glu-GSH axis plays a key role in aging and metabolism [19], age-dependent decline in extracellular thiol-disulfide balance, including the Cys/CySS redox couple, represents an important dimension of this axis in the context of organismal aging [226].

Changes in the Glu-GSH axis may also serve as potential biomarkers for early disease diagnosis. In various metabolic disorders [227,228] and neurodegenerative or psychiatric disorders [229,230], abnormal glutamate and GSH levels may precede clinical symptoms. Utilizing advanced imaging techniques such as PRESS and MEGA-PRESS to detect glutamate and GSH concentrations in vivo offers significant advantages, including non-invasiveness and high reproducibility, enabling dynamic monitoring of metabolic levels in living organisms. These tools provide a critical means for clinically assessing the status of the Glu-GSH axis and offer a novel technique for early disease screening.

Future research directions should prioritize: 1) Mechanistic dissection of the directionality and context-dependence of glutamate-GSH interconversion in specific disease stages and brain regions; 2) Longitudinal MRS studies correlating the Glu/GSH ratio with disease progression and treatment response; 3) Therapeutic strategies targeting the Glu-GSH axis, including combinations such as NAC supplementation with NMDA receptor modulation; and 4) Exploration of Glu-GSH dysregulation in additional organ systems including liver, kidney, and vasculature.

CRediT authorship contribution statement

Rui Wang: Funding acquisition, Writing – original draft, Writing – review & editing. Yanfei Li: Writing – original draft. Dafa Shi: Writing – original draft. Hongying Huang: Data curation. Zhongruowen Ren: Data curation. Yuxi Ge: Methodology. Yongmin Chang: Methodology, Software. Gen Yan: Funding acquisition, Writing – review & editing.

Declaration of competing interest

All authors have approved the final version of the manuscript and consent to its submission. This work has not been published or submitted for publication elsewhere, either in whole or in part, in another form or language.

We confirm that there are no conflicts of interest to declare.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (82503497, 82411540241), Science and Technology Plan Project of the Health Commission of Fujian Province (2025GGA100). Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5 were created by BioRender (www.biorender.com).

Contributor Information

Yongmin Chang, Email: ychang@knu.ac.kr.

Gen Yan, Email: gyan@stu.edu.cn.

Data availability

Data will be made available on request.

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Associated Data

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Data Availability Statement

Data will be made available on request.

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PERMALINK

The Glutamate–Glutathione axis in neuropsychiatric disorders and cancer: From shared mechanisms to non-invasive biomarkers

Rui Wang

Yanfei Li

Dafa Shi

Hongying Huang

Zhongruowen Ren

Yuxi Ge

Yongmin Chang

Gen Yan

Abstract

Graphical abstract

Highlights

1. Introduction

2. Metabolic networks of glutamate and GSH: from biosynthesis to interconversion

2.1. The γ-glutamyl cycle: central metabolic hub

Fig. 1.

2.2. Metabolism of glutamate

Fig. 2.

2.3. Metabolism of GSH

2.4. Interconversion between glutamate and GSH

2.4.1. Glutamate as a precursor for GSH synthesis

2.4.2. GSH degradation and glutamate recycling

3. Regulatory signaling pathways governing the Glu-GSH axis

Table 1.

3.1. Cascade amplification between glutamate and GSH

3.2. Regulatory signaling pathways (Fig. 3)

Fig. 3.

3.2.1. The Nrf2 signaling pathway

3.2.2. The AP-1 signaling pathway

3.2.3. The NF-κB signaling pathway

3.2.4. The glutamate/cystine antiporter system

3.2.5. The TGF-β/Smad signaling pathway

3.2.6. The p53 signaling pathway

4. Dysregulation of the Glu-GSH axis in disease: common mechanisms and disease-specific features

4.1. Overview of neuropsychiatric disorders: a shared mechanistic logic (Fig. 4)

Fig. 4.

Table 2.

4.1.1. Mechanism 1: Glutamate Excitotoxicity and Calcium-driven ROS generation

4.1.2. Mechanism 2: GSH depletion and failure of redox homeostasis

4.1.3. Mechanism 3: neuroinflammatory amplification

4.1.4. Mechanism 4: the glutamate Transporter-GSH feedback loop

4.1.5. Therapeutic implications of the mechanistic framework

4.2. Overview of cancer: a shared mechanistic logic (Fig. 5)

Fig. 5.

4.2.1. Promoting tumor cell proliferation

4.2.2. Reprogramming tumor metabolism

4.2.3. Regulating antioxidant defense

4.2.4. Modulating tumor cell signaling

4.2.5. Mediating tumor drug resistance

4.2.6. Facilitating immune evasion

5. Non-invasive detection of glutamate and GSH: MRS techniques and clinical translation

5.1. Advantages of MRI technique in clinical diagnosis

5.2. Detection of glutamate and GSH using MRS

5.2.1. Conventional MRS (PRESS)

5.2.2. MEGA-PRESS: enhanced specificity and original data

Fig. 6.

5.2.3. Other MRS sequences: STEAM, semi-LASER, SPECIAL

5.2.4. Multi-metabolite editing: the HERMES sequence

6. Conclusion and future perspectives

CRediT authorship contribution statement

Declaration of competing interest

Acknowledgements

Contributor Information

Data availability

References

Associated Data

Data Availability Statement

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