Disulfidptosis: a new target for central nervous system disease therapy

Abstract

Disulfidptosis is a pathologic process that occurs under conditions of NADPH deficiency and excess disulfide bonds in cells that express high levels of SLC7A11. This process is caused by glucose deprivation-induced disulfide stress and was first described by cancer researchers. Oxidative stress is a hypothesized mechanism underlying diseases of the central nervous system (CNS), and disulfide stress is a specific type of oxidative stress. Proteins linked to disulfidptosis and metabolic pathways involved in disulfidptosis are significantly associated with diseases of the CNS (neurodegenerative disease, neurogliomas and ischemic stroke). However, the specific mechanism responsible for this correlation remains unknown. This review provides a comprehensive overview of the current knowledge regarding the origin elements, genetic factors, and signaling proteins involved in the pathogenesis of disulfidptosis. It demonstrates that the disruption of thiometabolism and disulfide stress play critical roles in CNS diseases, which are associated with the potential role of disulfidptosis. We also summarize disulfidptosis-related drugs and highlight potential therapeutic strategies for treating CNS diseases. Additionally, this paper suggests a testable hypothesis that might be a promising target for treating CNS diseases.

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Frontiers in Neuroscience 01 frontiersin.org
Disulfidptosis: a new target for
central nervous system disease
therapy
JingChang
1, DanhongLiu
2,3, YuqiXiao
1, BoyaoTan
1, JunDeng
4,
ZhigangMei
5 and JunLiao
5,6*
1 College of Medicine, Hunan University of Traditional Chinese Medicine, Changsha, China, 2 Institute
of Clinical Pharmacology of Chinese Materia Medica, Hunan Academy of Chinese Medicine,
Changsha, China, 3 Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine
(The Aliated Hospital of Hunan Academy of Chinese Medicine), Changsha, China, 4 Department of
Neurology, Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine,
Changsha, China, 5 Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western
Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese
Medicine, Changsha, China, 6 Vascular Biology Laboratory, Medical College, Hunan University of
Chinese Medicine, Changsha, China
Disulfidptosis is a pathologic process that occurs under conditions of NADPH
deficiency and excess disulfide bonds in cells that express high levels of SLC7A11.
This process is caused by glucose deprivation-induced disulfide stress and was first
described by cancer researchers. Oxidative stress is a hypothesized mechanism
underlying diseases of the central nervous system (CNS), and disulfide stress is
a specific type of oxidative stress. Proteins linked to disulfidptosis and metabolic
pathways involved in disulfidptosis are significantly associated with diseases of the
CNS (neurodegenerative disease, neurogliomas and ischemic stroke). However, the
specific mechanism responsible for this correlation remains unknown. This review
provides a comprehensive overview of the current knowledge regarding the origin
elements, genetic factors, and signaling proteins involved in the pathogenesis of
disulfidptosis. It demonstrates that the disruption of thiometabolism and disulfide
stress play critical roles in CNS diseases, which are associated with the potential
role of disulfidptosis. Wealso summarize disulfidptosis-related drugs and highlight
potential therapeutic strategies for treating CNS diseases. Additionally, this paper
suggests a testable hypothesis that might bea promising target for treating CNS
diseases.
KEYWORDS
disulfidptosis, thiometabolism, thiol/disulfide, central nervous system diseases,
therapy
1 Introduction
Cell death maintains balance in morphogenesis by clearing damaged or obsolete cells
during a state of physical health or illness (Newton etal., 2024). Programmed cell death occurs
during the development of normal neurons to establish a spatial and temporal framework.
Additionally, various types of cell death, such as pyroptosis, apoptosis, ferroptosis, and
necrosis, which involve abnormal signaling cascades and interrelationships, are involved in
the pathological mechanism of neurological disorders (Moujalled etal., 2021). Recently, a
novel form of programmed death called disuldptosis was proposed, the mechanism of which
is the focus of cancer research. Disuldptosis cell death genes are potentially linked to various
cancer types and may function as candidate genes for cancer diagnosis, prognosis, and
therapeutic biomarkers (Liu and Tang, 2023). Copper death genes may beassociated with
various cancer types and could function as potential biomarkers for cancer diagnosis,
OPEN ACCESS
EDITED BY
David Mokler,
University of New England, UnitedStates
REVIEWED BY
Yuanbo Pan,
Zhejiang University, China
Tang Tao,
Sun Yat-sen University Cancer Center
(SYSUCC), China
*CORRESPONDENCE
Jun Liao
liaojun@hnucm.edu.cn
RECEIVED 20 October 2024
ACCEPTED 27 January 2025
PUBLISHED 05 March 2025
CITATION
Chang J, Liu D, Xiao Y, Tan B, Deng J,
Mei Z and Liao J (2025) Disulfidptosis: a new
target for central nervous system disease
therapy.
Front. Neurosci. 19:1514253.
doi: 10.3389/fnins.2025.1514253
COPYRIGHT
© 2025 Chang, Liu, Xiao, Tan, Deng, Mei and
Liao. This is an open-access article distributed
under the terms of the Creative Commons
Attribution License (CC BY). The use,
distribution or reproduction in other forums is
permitted, provided the original author(s) and
the copyright owner(s) are credited and that
the original publication in this journal is cited,
in accordance with accepted academic
practice. No use, distribution or reproduction
is permitted which does not comply with
these terms.
TYPE Review
PUBLISHED 05 March 2025
DOI 10.3389/fnins.2025.1514253

Chang et al. 10.3389/fnins.2025.1514253
Frontiers in Neuroscience 02 frontiersin.org
prognosis, and treatment (Liu and Tang, 2022). Boyi Gan and
colleagues dened disuldptosis in 2023 as high SLC7A11 expression
and NADPH depletion, resulting in the suppression of cystine/
cysteine conversion under conditions of glucose starvation, which
leads to disulde bond accumulation, disulde stress, and collapse of
the cytoskeleton. Pyroptosis is an immunogenic programmed cell
death that eectively activates tumor immunogenicity and reprograms
the immunosuppressive microenvironment to improve cancer
immunotherapy. However, an overexpression of SLC7A11 promotes
the biosynthesis of glutathione to maintain redox balance and combat
pyroptosis (Zhu etal., 2024b). Apoptosis occurs in development,
tissue homeostasis, and immune function. Unlike disuldptosis,
apoptosis does not typically involve protein aggregation induced by
oxidative stress or is centered around dysfunction of the actin network
(Xiao etal., 2024). Ferroptosis is a novel form of programmed cell
death characterized by iron-dependent oxidative damage, lipid
peroxidation, and the accumulation of reactive oxygen species (Zuo
etal., 2022). Disuldptosis is a form of cell death caused by oxidative
reductive imbalance resulting from amino acid metabolism and
glucose metabolism disorders (Wang etal., 2024). In the physiological
system, the thiol disulde redox involves the reduction of disulde to
thiol and the oxidation of thiol to disulde (Ghosh et al., 2023).
Disuldptosis is caused by the imbalance between thiols and
disuldes, resulting in disulde stress. In contrast, ferroptosis is caused
by lipid peroxidation and excessive oxidative stress due to iron ion
deposition. Some researchers speculate that disuldptosis is a specic
form of oxidative stress-induced cell death that corresponds to
diseases of various systems in the humaccn body, such as the
respiratory, digestive, urinary, and reproductive systems (Chen
etal., 2024).
e prevalence of central nervous system diseases (CNSD),
such as brain tumors, neurodegenerative diseases (Alzheimer’s
disease, Parkinson’s disease, etc.), and ischemic stroke has
increased signicantly, severely aecting general health conditions
and imposing signicant nancial and societal strain on
individuals aected by these conditions (Zhang X. etal., 2021).
e accumulation of high levels of reactive oxygen species,
neurotoxic substances, and inammatory cytokines forms the
pathological mechanism underlying CNSD, which results in
dysfunction of the nervous system and the development of
therapeutic targets for neurological diseases (Patel, 2016). A study
revealed that deleting ETHE1, a mitochondrial sulfur dioxygenase
involved in sulde catabolism in encephalopathy, leads to fatal
sulde toxicity; these ndings suggest that most mammalian
brains have a very limited ability to break down sulde and that
sulde accumulation can cause brain damage (Tiranti etal., 2009).
Previously, the processes and causes of the diverse pathological
mechanisms underlying CNS disorders were elusive; Central
nervous system (CNS)-related diseases exhibit a high mortality
rate and pose signicant risks to both physical and mental health,
making them a critical focus of research (He et al., 2024).
erefore, by conducting a literature review, we propose that
thiometabolism is closely related to specic cellular redox
reactions that depend on the thiol/disulde ratio. A detailed
mapping of disuldptosis in nervous system disease may reveal the
network regulating the crucial targets of the pathological process
and provide new insights into potential clinical treatment
directions for neurological disorders.
2 Research progress on factors related
to disulfidptosis in the CNS
2.1 Physiological function of sulfur
Redox (oxidation–reduction) reaction is the core of the
existence of life. The reactants namely, oxygen, nitrogen, and
sulfur, mediate the redox control of a series of important cellular
processes (Sies etal., 2024). Sulfur is present mainly in the form
of compounds in the human body and is involved in various
biological processes, including protein synthesis, energy
metabolism, and oxidation–reduction equilibrium (Fan etal.,
2023). First, sulfur is involved in the synthesis of sulfur-
containing amino acids, such as cystine, cysteine, and methionine,
as well as sulfuric acid, which play a vital role in sustaining
normal physiological functions (Chatterjee and Hausinger, 2022).
The mechanism by which cells maintain redox homeostasis or
function in the antioxidant defense system strongly depends on
the regulatory reactivity of the sulfur atoms inside or derived
from cysteine and methionine (Miller and Schmidt, 2020). The
antioxidant capacity of sulfur-containing amino acids, such as
cysteine, contributes to their ability to neutralize reactive oxygen
species (ROS) (Stipanuk, 2020). Additionally, two molecules of
cysteine are converted into cystine through the action of
dehydrogenase in the neuronal redox reaction, in which
sulfhydryl, a functional group of thiols in cysteine, leads to the
formation of disulfide bonds (Stipanuk, 2020). Proteins
containing thiol-disulfide bonds play crucial roles in regulating
cellular redox homeostasis and serve as diagnostic markers for
diseases influenced by redox conditions (Hanchapola et al.,
2023). The formation of protein disulfide bonds serves as an
indicator of oxidative stress linked to neurodegeneration
(Landino etal., 2014). Second, sulfur atoms are closely associated
with the synthesis of iron–sulfur proteins, which are essential and
minimally functional proteins of mitochondria; abnormal iron–
sulfur clusters lead to deficiencies in target proteins, including
complexes I, II, and III; aconitase; and lipoic acid (Selvanathan
and Parayil, 2022). Third, in cellular metabolism, sulfur helps
maintain redox balance, which results in the formation of a
cellular antioxidant system that mediates intercellular and
intracellular signaling (Moreno etal., 2014). Some studies have
suggested that disulfide stress may bea distinct form of oxidative
stress in cases of acute inflammation involving protein cysteine
and gamma-glutamylcysteine, as well as cysteine/cystine
oxidation. However, no alterations in glutathione (GSH)
oxidation or protein GSH were observed (Ward and DeNicola,
2019). During cellular reduction and oxidation, the
transformation of sulfur-containing proteins and the dynamic
balance of thiol-disulfide bonds are associated with antioxidant
defense in the development of several psychiatric disorders
(Messens and Collet, 2013; Ergin etal., 2023) (Figure1).
2.2 Elements of disulfidptosis in the CNS
e elements of disuldptosis in the CNS involve the following
factors: the Xc-system, the cystine/cysteine balance, glucose
starvation, and NADPH depletion.

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Frontiers in Neuroscience 03 frontiersin.org
2.2.1 Cystine/glutamate transporter (Xc-system)
e cystine/glutamate transporter (Xc-system) comprises
disulde-bonded heterodimers solute carrier family 7 member 11
(SLC7A11, also known as xCT) and SLC3A2, which form a membrane
transport protein system that is responsible for transporting
extracellular cystine and intracellular glutamate across the cell
membrane at a 1:1 ratio; this process plays a crucial role in signaling
transmission during antioxidant defense in the CNS (Bridges etal.,
2012). e sudden hypoxia of neurons during a stroke results in a
signicant release of glutamate, causing hypoxic depolarization and
subsequent rapid cell death. e latency of glutamate-driven
Alzheimer’s disease events signicantly inuences the degree of
subsequent tissue damage (Verbruggen etal., 2022; Heit etal., 2023).
ese ndings indicate that glutamate self-stabilization and balance
of oxidative stress are important tasks for systemic Xc-completion in
the nervous system (Dahlmanns etal., 2023). Glutamate is the primary
neurotransmitter that stimulates neurons in the central nervous
system (CNS), where it initially begins fast signaling at the synapse
and is subsequently reabsorbed by peripheral glial cells. For example,
transporters 1 (EAAT1) and 2 (EAAT2), which take up synaptic
glutamate to maintain its normal extracellular levels found in
astrocytes, prevent glutamate accumulation in the synaptic gap and in
the nervous system. Upregulation of SLC7A11 increases glutamate
output in cells, whereas downregulation of EAAT reduces intracellular
glutamate input (Dahlmanns etal., 2023). On the other hand, the
function of xCT is to introduce cysteine for glutathione biosynthesis
and antioxidant defense (Wang etal., 2023). Under glucose starvation
conditions, damage to the pentose phosphate pathway can lead to a
decrease in its metabolic product NADPH, resulting in a reduction in
NADPH electron donors that prevent cystine from being converted
to cysteine. erefore, overexpression of the Xc system can induce
inappropriate accumulation of cystine in the cytoplasm, leading to
disulde stress (Zhong etal., 2023). ese ndings conrm the theory
that Xc-system serves as a link between inammation and glutamate
excitotoxicity and that xCT might act as a target for reducing
glutamate excitotoxicity in neurodegenerative diseases under
inammation (Pampliega et al., 2011). Consequently, abnormal
mechanisms of cystine and glutamate exchange make the Xc-system
a potential contributor to many CNSD (Adla etal., 2024).
2.2.2 Cystine/cysteine balance
Cystine and cysteine contain disulde bonds and thiols,
respectively, and can undergo interconversion. Cysteine is an integral
part of the main antioxidant GSH and acts as a potent antioxidant in
the brain, playing a crucial role in protein synthesis and redox
homeostasis (Paul etal., 2018). e conversion of cystine to cysteine
is required to maintain the thiol/disulde redox equilibrium within
cells (Go and Jones, 2005). Cystine and other disulde compounds
accumulate in large quantities under conditions of high SLC7A11
expression, glucose deprivation, and NADPH depletion, resulting in
disulde stress (Liu X. etal., 2024). Dynamic regulation of thiol/
disulde homeostasis is essential for various metabolic processes,
including signal mechanisms, inammation, and antioxidant defense
(Erenler and Yardan, 2017). iol/disulde is a critical component of
FIGURE1
Physiological function of sulfur. Sulfur mainly exists in the form of compounds in the human body and participates in various biological processes. First
of all, sulfur also participates in antioxidant defense and detoxification processes. Cysteine is an important antioxidant that can neutralize reactive
oxygen species, thereby reducing the damage of oxidative stress to cells iron–sulfur proteins are minimally functional proteins of mitochondria;
Secondly, Cystine and cysteine, two sulfur-containing amino acids, participate in the formation of disulfide bonds in proteins, stabilizing their three-
dimensional structure and function. The formation of disulfide bonds can maintain the normal conformation of proteins, thereby ensuring their normal
function; Finally, sulfur also participates in the synthesis of iron sulfur proteins and is an essential component of the electron transport chain. It plays a
critical role in biological processes such as cellular respiration and photosynthesis.

Chang et al. 10.3389/fnins.2025.1514253
Frontiers in Neuroscience 04 frontiersin.org
the antioxidant defense system and is necessary for maintaining the
intracellular redox balance and for the diagnosis and prognostic
assessment of potentially lethal diseases (Chatterjee and Hausinger,
2022). Restoring cysteine homeostasis has therapeutic benets in
neurodegenerative diseases (Paul etal., 2018). erefore, the level of
cystine/cysteine, which can beused to detect thiol/disulde, is an
important indicator of disulde stress.
2.2.3 Glucose starvation and NADPH depletion
Glucose is the main source of NADPH production through the
pentose phosphate pathway (PPP) (Ying etal., 2021). Nicotinamide
adenine dinucleotide phosphate (NADPH) is synthesized by four
enzymes in mammalian cells, including isocitrate dehydrogenase,
malic enzyme glucose-6-phosphate dehydrogenase (G6PD), and
PGD; the oxidized form is NADP+. Glucose-6-phosphate
dehydrogenase (G6PD), which serves as a primary source of NADPH
oxidase, a reducing agent, and a hydrogen ion donor in the reduction
reaction, plays multiple roles in energy supply, signaling, and
antioxidant reactions (Stanton, 2012; Zhang and Peng, 2014).
NADPH, as a coenzyme, can act as a reducing agent for the conversion
of cystine to cysteine, playing a role in the transfer of hydrogen in the
reduction reaction (Mi etal., 2024). Glucose starvation damages the
glycolysis and pentose phosphate pathways, leading to an increase in
reactive oxygen species (ROS) production and damage to the
antioxidant system, resulting in oxidative stress, redox imbalance, and
cell death (Ren and Shen, 2019). When glucose starvation occurs, a
large amount of NADPH is consumed, and the NADP+/NADPH ratio
signicantly increases. Cystine in SLC7A11-overexpressing cells
cannot bereduced to cysteine, resulting in increased levels of disulde
and disuldptosis (Liu etal., 2023a). For a long time, glucose has been
an indispensable fuel for the brain, as it can perform many key
functions, including producing ATP, managing oxidative stress, and
synthesizing neurotransmitters, neuromodulators, and structural
components (Dienel, 2019). Dysfunction of glucose metabolism in the
entire brain or specic cell types, including ischemic brain injury and
neurodegenerative diseases, is closely related to neurological
pathology (Zhang S. etal., 2021). Under neuropathological conditions,
mitochondrial defects oen lead to electron transfer processes and
reduced NADPH oxidase activity, resulting in increased reactive
oxygen species production, which weakens the redox buering
capacity of the cell and may damage key enzymes involved in energy
metabolism (Tang, 2020).
Disuldptosis is associated with the equilibrium of some redox
regulatory pairs, such as cystine vs. cysteine and NADP+ vs. NADPH
(Wang etal., 2024). During disulde reduction, NADPH plays a
crucial role by transferring electrons and serves as a precursor for
synthesizing enzymes for TRX-disulde reductase (TrxRs) and
glutathione-disulde reductase (Gsrs) (Miller etal., 2018). NADPH
participates in the generation of reducing antioxidants, such as GSH
and thioredoxin (Trx), to prevent redox stress. According to some
researchers, NADPH is a double-edged sword in redox reactions;
although it inhibits oxidative stress in the cellular antioxidant system,
it serves as a substrate for ROS production by NADPH oxidases
(NOx), exacerbating oxidative damage (Liu etal., 2021). e cystine/
cysteine system strongly regulates the mechanism of disuldptosis,
where the intracellular transport of cysteine is regulated by the Xc-
system, and the conversion of cystine and cysteine is mediated by
NADPH electron delivery. Additionally, disuldptosis requires high
consumption or a low supply of NADPH, high expression of SLC7A11,
and glucose starvation.
2.3 Disulfide stress in disulfidptosis
Disulde bonds play important roles in maintaining the rich
characteristics of protein structure, stability, and function (Robinson
and Bulleid, 2020). Disuldptosis is a regulatory form of cell death
induced by disulde stress (Liu etal., 2023a), which is caused by an
imbalance of the intracellular glutathione and thioredoxin antioxidant
systems, leading to the accumulation of disulde bonds.
2.3.1 Disulfide stress eector protein: F-actin
e cytoskeleton is a three-dimensional structural network
composed of interwoven protein bers, primarily consisting of
microtubules, microlaments, and intermediate bers. It maintains
the unique shape of cells and is associated with cell movement
(Schmid etal., 2024; Haseena etal., 2024). F-actin is an important
component of microlaments (MFs), which are spiral bers composed
of actin polymers that are ubiquitous in eukaryotic cells. When the
actin monomer G-actin binds to ATP, the monomer is assembled into
the polymer F-actin. When ATP is hydrolyzed to ADP, F-actin is
depolymerized (Dominguez and Holmes, 2011). e proper function
of actin strongly depends on its oxidation–reduction state; under
oxidative stress, actin can become oxidized and undergo alterations in
its shape and function (Rouyère etal., 2022). e cysteine residue in
actin functions as a sensor for oxidative stress, resulting in a high level
of sensitivity to ROS, RNS, and lipid peroxidation (Farah and Amberg,
2007). Under invitro conditions, Cys 374 of actin has the highest
reactivity, which leads to the formation of intramolecular disulde
bonds with Cys 285 or other actin molecules (Farah etal., 2011).
F-actin plays a vital role in dendritic spines, maintaining synaptic
structure and function, whereas disulde stress may cause the collapse
of the F-actin cytoskeleton, which is the pathological outcome of
disuldptosis (Li etal., 2024). In AD patients, the actin cytoskeleton
is lost from synapses. Glutamatergic receptor numbers,
neurotransmission, and synaptic strength are all aected when the
actin cytoskeleton is lost, compromising synaptic integrity (Haseena
etal., 2024).
2.3.2 Disulfide stress-related Rac1-WRC-Arp2/3
signaling pathway
Rac1 (a type of Rho GTPase), a fundamental regulatory factor of
the actin cytoskeleton, plays important roles in cell movement,
polarity, and migration (Bailly etal., 2024). Furthermore, Rac1 plays
a crucial role in specic brain functions, including neuronal migration,
synaptic plasticity, and memory formation, through its regulation of
actin dynamics in neurons. Abnormal expression and activity of Rac1
have been observed in various neurological disorders (Wang X. etal.,
2020). Waves exist in pentamer complexes known as WAVE regulatory
complexes (WRCs), including ABIs, NAP1 (also known as NCKAP1),
CYFIPs, and HSPC300 (Alekhina etal., 2017). Preliminary CRISPR
screening and functional studies revealed that inactivation of the
WRC can promote actin polymerization, regulate actin cytoskeletal
dynamics, and inhibit disuldptosis (Liu etal., 2023a). WRCs also play
crucial roles in regulating actin cytoskeletal dynamics and remodeling
eukaryotic cells, including the regulation of dendritic spine growth

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Frontiers in Neuroscience 05 frontiersin.org
and presynaptic assembly, which are linked to various brain diseases
(Ibarra etal., 2005; Han and Ko, 2023). e removal of NCKAP1 and
other WRC proteins weakens disulde stress, whereas the excessive
expression of constitutively activated Rac stimulates disuldptosis in
a WRC-dependent manner (Liu etal., 2023a). e NCKAP1 gene may
regulate the expression of actin by modulating intracellular disulde
levels and the stability of the actin cytoskeleton. Rac1 can bind to
WRC, inducing a conformational change that promotes the activity of
the Arp2/3 complex, leading to F-actin nucleation and lamellipodia
formation. is, in turn, facilitates actin polymerization and the
formation of lamellipodia (Begemann etal., 2021). Consequently, the
Rac1-WRC pathway facilitates the formation of disulde bonds,
thereby mediating actin polymerization in disulde stress (Li
etal., 2024).
2.3.3 Disulfide stress-related disulfide bond
regulatory system: the Trx and GSH/Grx systems
Thioredoxin (Trx) and the GSH/Grx system play important
roles in maintaining redox balance in the brain, which is a tissue
prone to oxidative stress due to its high energy demands. These
two disulfide reductase systems are active in various regions of
the brain and are considered key antioxidant systems in the
central nervous system (Ren et al., 2017). The pathological
mechanism underlying disulfidptosis is associated with a redox
imbalance state, which involves the formation of disulfide bonds
by sulfur oxidase and sulfate lyase, ultimately leading to disulfide
stress (Wang etal., 2023). To suppress disulfidptosis, two protein
repair systems, the Trx system and the glutaredoxin (Grx) system,
balance the conversion of thiol groups and disulfide bonds. Both
systems are essential for defending against oxidative damage
through their disulfide reductase activity, which regulates the
dithiol/disulfide balance (Shahriari-Farfani etal., 2019).
2.3.3.1 Trx system
e Trx system is composed of Trx, thioredoxin reductase (TrxR),
and NADPH (Bjørklund etal., 2022). Chloroplastic thioredoxins (Trxs),
a family of thiol-disulde oxidoreductases, are the products of two
mammalian genes, txn1 and txn2, which encode the cytoplasmic and
mitochondrial Trx isoforms, respectively (Kang etal., 2019). Trx regulates
redox equilibrium in mammalian cells and can betriggered by multiple
factors, including oxidative stress, inammation, aging, and autoimmune
disorders (Yang etal., 2024) Equations [1–3]. e Trx system reduces
cystine accumulation by regulating cystine/cysteine balance, thereby
preventing disuldptosis (Kang et al., 2019). Trx catalyzes the thiol-
disulde exchange reaction, which involves electron transfer between Trx
and its target protein. In subsequent programs, NADPH, as an electron
donor and a mixed disulde bond (Figure3) is reduced by TrxR, and the
reaction cycle can berepresented as follows (Yang etal., 2024; Li etal.,
2019; Zheng Z. etal., 2018).
( )
Trx SH 2 Protein S2−+ −
⇌ Trx – S2 + Protein – (SH)2 (1)
TrxR S2 NADPH H
+
−+ + ⇌ TrxR – (SH)2 + NADP+ (2)
( )
Trx S2 TrxR SH 2−+ − ⇌ TrxR – S2 + Trx – (SH)2 (3)
2.3.3.2 The GSH/Grx system
e GSH/Grx system plays key roles in controlling signaling and
imbalance in thiol-disulde redox homeostasis and redox reactions,
which are linked to the development and progression of oxidative
stress-related disorders (Chai and Mieyal, 2023), and the GSH-Grx
system consists of NADPH, glutathione reductase, GSH and Grx (Lu
and Holmgren, 2014). GSH-Grx belongs to the Trx protein family
and facilitates the reduction of disulde bonds to maintain redox
homeostasis. ere are two main forms of Grx: Grx1 is found in the
cytoplasm and accepts electrons from GSH, whereas Grx2 is located
in the mitochondria and nucleus of mammalian cells and can obtain
electrons from GSH and TrxR2 (Fernandes and Holmgren, 2004).
Like thioreductase, GSH can act as a dithiol reducing agent
[7CC4]
.
Glutathione (GSH) is an important, naturally occurring small-
molecule thiol composed of glutamate, cysteine, and glycine. GSH
has antioxidant and detoxifying activities (Liu X. etal., 2020) and
may also participate in physiological processes such as protein
folding, thiol maintenance from oxidation, and cell cycle regulation
(Averill-Bates, 2023). GSH is an important mechanism for
maintaining brain redox balance and regulating several proteins that
are crucial for neurobiological processes (Ogata etal., 2021). GSH is
present in high concentrations in the brain (about 1–3 mM). Studies
have shown that the Trx and GSH/Grx systems are specic to
dierent organelles in neurons and glial cells and regulate redox
signaling and that thiol-disulde bond conversion (GSH) occurs in
two states: oxidized and reduced (Horibe etal., 2001). e reduced
form of GSH is generated in a reaction catalyzed by glutathione
synthetase (GSS) and is transformed into glutathione disulde
(GSSG) through the oxidation of sulydryl residues. GSSG is then
reduced back to GSH through interaction with glutathione reductase
(the normal ratio of GSH/GSSG is about 100:1), using NAPDH as a
cofactor (Couto etal., 2016; Georgiou-Sias and Tsisoglou, 2023).
erefore, the GSSG-to-GSH ratio is a measure of the cellular redox
status (Moujalled etal., 2021). Studies have shown that the redox
couples cysteine/cystine (Cys/CySS) and Trx (SH)2 [reduced Trx/
TrxSS] [oxidized Trx], as well as GSH [reduced glutathione] and
GSSG [oxidized glutathione] are critical components of the thiol/
disulde redox system (Circu and Aw, 2011) (Figure3). Oxidative
stress caused by GSH deciency is common in many CNS diseases
(Adla et al., 2024), and supplementation with n-acetylcysteine
(NAC) can prevent GSH deciency as an independent treatment
(Rumann and Wendel, 1991). Under oxidative stress, cysteine
residues (-SH) and GSH on proteins create a reversible post-
translational alteration called S-glutathionylation (Protein-SSG)
(Dominko and Đikić, 2018). Grx is an important component of the
thiol-disulde oxidoreductase family, which catalyzes redox
reactions between GSH and GSSG (Fernandes and Holmgren, 2004;
Mustafa etal., 2021). Cysteine-179 of the β subunit of the inhibitory
κB kinase (IKK) signaling complex is a core target of
S-glutathionylation. Glutathione reductase (Grx) reverses the
S-glutathionylation of IKK-β Cys179, thus restoring kinase activity
(Reynaert etal., 2006).
Trx and Grx systems are widely distributed in the brain and
participate in the formation, transfer, and isomerization of disulde

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bonds through thiol-disulde exchange reactions (Sousa etal., 2019;
Aon-Bertolino etal., 2011). Trx and GSH/Grx systems are distributed
in the cortex, striatum, hippocampus, etc., and play crucial roles in the
cellular defense against oxidative stress in hypoxia-induced ischemic
injury. Additionally, redox reactions are regulated by the
oxidoreductases Trx and Grx, which are specic targets of signal
transduction pathways associated with the stress response (Jiménez
etal., 2024). Moreover, Trx and Grx preserve the reduced state of the
cell by reducing oxidized thionine residues in actin to protect the
morphology of the cytoskeleton (Meyer etal., 2012). Consequently,
the Trx and Grx systems maintain the balance of thiol-disulde
interactions in the reduction/oxidation conversion of protein forms,
which act as target signaling pathways to regulate disulde stress and
may act as crucial triggers to suppress disuldptosis.
3 Disulfidptosis-related programmed
cell death
ere are currently many types of cell death, such as pyroptosis,
apoptosis, and autophagy, but only ferroptosis and cuproptosis are
related to disuldptosis. e cell death in three types of cell death,
namely disuldptosis ferroptosis, and cuproptosis, is related to
redox homeostasis. One or more key factors may act as switches for
cells to oscillate between the three modes of cell death. It is
speculated that this common switch is cystine to cysteine (Wang
etal., 2024). Recent research has found that a new type of carrier
free nanoparticle has been developed to eectively treat cancer
through the combined eect of ferroptosis and cuproptosis (Zhu
etal., 2024a).
FIGURE2
The similarities and dierences between disulfidptosis and ferroptosis in CNS. SLC7A11 is the catalytic subunit of the XcT system, which absorbs
cysteine from the extracellular environment and converts it into cysteine to synthesize GSH. GPX4 uses GSH to reduce LOOH to LOH, preventing lipid
peroxidation and inhibiting ferroptosis. Meanwhile, GSH is oxidized to GSSG. Then GSSG is converted back to GSH through GR mediated reduction
reaction, consuming NADPH in the process. Under conditions of glucose starvation and high SLC7A11, the pentose phosphate pathway is blocked,
resulting in reduced NADPH production, hindered conversion of cysteine to cysteine, accumulation of cysteine and other disulfides, triggering the
formation of abnormal disulfide bonds in redox sensitive proteins, ultimately leading to the rupture of the cytoskeleton and cell disulfidptosis. On the
other hand, due to NADPH depletion, cystine cannot be converted into cysteine, resulting in reduced synthesis of GSH and generation of lipid
peroxides, leading to ferroptosis. Abbreviations: NADP+: nicotinamide adenine dinucleotide phosphate, reduced form; NADPH: nicotinamide adenine
dinucleotide phosphate; GSH: glutathione; GPX4: Glutathione peroxidase 4; LOOH: lipid hydroperoxides; LOH: lipid alcohols; GSSG: glutathione
disulfide; GR: glutathione disulfide reductase.

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FIGURE3
Mechanisms of disulfidptosis. By analyzing the relationships among the expression level of SL7A11, NADPH metabolism, and glucose levels, the factors
necessary for cell death were explored. When SLC7A11 and glucose are overexpressed or decreased simultaneously, cell survival occurs. However, only
when high SLC7A11, low glucose, and NADPH depletion are present simultaneously can they lead to cystine/cysteine conversion disorders, the
accumulation of disulfides, and ultimately disulfidptosis. When glucose starvation blocks the production of NADPH through the pentose phosphate
pathway, a large amount of intracellular cysteine input through high expression of SLC7A11 depletes NADPH. Owing to the insolubility of cystine,
NADPH is needed as a reducing force to decompose it into cysteine. The low supply of NADPH also blocks the process of cystine conversion to
cysteine, leading to a large accumulation of cystine and activating the Rac1-WRC-Arp2/3 pathway. Abnormal disulfide bonds are formed in actin
cytoskeleton proteins, and F-actin is broken down, ultimately leading to disulfidptosis. Moreover, depletion of NADPH can also hinder GSH/GSSG
conversion and Trx-(SH) 2/Trx-S2 conversion, ultimately leading to an imbalance in the intracellular glutathione and thioredoxin antioxidant systems.
Abbreviations: GLUT: glucose transporter; Trx-(SH) 2: thioredoxin reduced; Trx-S2 thioredoxin oxidized; NADP+: nicotinamide adenine dinucleotide
phosphate, reduced form; NADPH: nicotinamide adenine dinucleotide phosphate; G6P: glucose-6-phosphate dehydrogenase; 6PG:
6-phosphogluconate; R5P: ribose-5-phosphate dehydrogenase; GSH: glutathione; GSSG: glutathione oxidized.

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3.1 Ferroptosis
e DIXON group rst postulated that ferroptosis, a type of
programmed cell death initiated by lipid peroxidation, depends on
iron (Seibt etal., 2019). Some proteins implicated in disuldptosis are
also associated with the initiation and progression of ferroptosis. First,
System Xc (cystine/glutamate antiporter) is constructed from the
heavy chain SLC3A2 and light chain SLC7A11 (xCT) (Tu etal., 2021).
SLC7A11, following its overexpression, imports cystine to suppress
ferroptosis through GSH biosynthesis and antioxidant defense
(Koppula et al., 2021). Moreover, the upregulation of SLC7A11
contributes to the emergence of disuldptosis by increasing the input
of cystine and causing an imbalance in the cystine/cysteine ratio,
which in turn promotes disuldptosis (Liu X. etal., 2024). Second,
NADPH is required for inhibiting lipid oxidation and serves as an
indicator of ferroptosis in various types of tumor cells (Wang etal.,
2023). NADPH depletion also induces a high cystine/cysteine ratio,
leading to disulde stress, which facilitates disuldptosis (Dixon etal.,
2012). Another relevant mechanism includes the disulde-glutathione
redox couple (GSH/GSSG) (Ursini and Maiorino, 2020). GSH inhibits
cellular ferroptosis by stimulating the production of glutathione
peroxidase (GPX4) to reduce lipid peroxidation products (Dixon
etal., 2012). Additionally, GSH and GSSG act as crucial constituents
of the thiol/disulde redox system (Circu and Aw, 2011), which may
beclosely related to disulde stress. During ferroptosis, NADPH is a
key regulator that acts as a cofactor and functions along with GRX to
reverse the conversion of GSSG to GSH, sustain the balance between
GSH and GSSG, and inhibit lipid peroxidation damage (Seibt etal.,
2019; Lu, 2013). During signal cascades, enzymes in the Trx family
(Trxs and Grxs) also play a signicant role in maintaining the balance
of oxidation–reduction reactions, such as the ratio of GSH/GSSG, by
regulating thiol/disulde conversion (Aoyama, 2021; Musaogullari
and Chai, 2020). Consequently, the regulation of the expression of the
membrane transporter SLC7A11, NADPH depletion because of
glucose starvation, and subsequent disruption of the balance of thiol/
disulde bonds may serve as a common link between disuldptosis
and ferroptosis (Figure 2), potentially involving intersecting
molecular pathways.
3.2 Cuproptosis
Cuproptosis is a newly recognized type of cell death, and the
process involves reliance on copper, accumulation of proteins
modied with fatty acids, and reduction of Fe-S cluster proteins
(Chen etal., 2022). During cuproptosis, copper accumulation may
beregulated by ferredoxin 1 (FDX1) and lipoic acid synthase (LIAS)
(Tsvetkov etal., 2022). FDX1 interferes with redox homeostasis to
induce cuproptosis in endometriosis, which is mediated by glucose-
6-phosphate (G6PD); these changes suppress the proliferation and
metastasis of endometrial cells (Lu et al., 2023). Moreover, a
previous study revealed that G6PD signicantly aects REDOX
homeostasis by regulating glycolytic ux through the pentose
phosphate pathway (PPP) (Garcia etal., 2021). It also produces
NADPH, which is an essential cofactor for glutathione (GSH/
GSSG) conversion (Luzzatto etal., 2020). Some related studies have
reported that p53 regulates the metabolism of glycolysis and
oxidative phosphorylation by acting as the rate-limiting enzyme of
the PPP by binding to glucose-6-phosphate dehydrogenase (G6PD)
(Vousden and Ryan, 2009). Furthermore, p53 suppresses NADPH
production by inhibiting malic enzyme or G6PD (Jiang etal., 2011).
Consequently, ferroptosis, cuproptosis, and disuldptosis may
involve interrelated crosstalk mechanisms involving glycolysis and
oxidative phosphorylation in the context of circulatory disturbance.
4 Research on
disulfidptosis-associated CNS disease
4.1 Neurodegenerative disease
4.1.1 Alzheimer’s disease
Alzheimer’s disease (AD) is a prevalent condition characterized
by progressive degeneration of the brain, which may involve an
increase in oxidative stress, a decrease in antioxidant enzymes, and
consequent disruption of the redox dynamic balance (Yu etal., 2024).
Eight disuldptosis-related genes (DRGs) signicantly aect the
beginning and progression of AD. Specically, the activity of the
SLC7A11, SLC3A2, and GYS1 genes increases, whereas the activity of
the OXSM, NUBPL, NDUFA11, NCKAP1, and LRPPRC genes
decreases (Zhu etal., 2023) (Table1). Additionally, a dierential
analysis of the gene expression matrix of AD revealed seven
characteristic genes associated with the breakage of disulde bonds,
including MYH9, IQGAP1, ACTN4, DSTN, ACTB, MYL6, and
GYS1, which accurately assess subtypes of AD and diagnose AD (Ma
etal., 2023). Some studies have suggested that dynamic disruption of
the actin cytoskeleton occurs during the progression of AD. A detailed
understanding of the mechanisms of the actin cytoskeleton can pave
the way for developing innovative synapse-targeted therapeutic
interventions and identifying new biomarkers to monitor synaptic loss
in Alzheimer’s disease (Pelucchi etal., 2020). ioredoxin-1 (Trx-1) is
a multifunctional molecule that has anti-inammatory properties in
human tissues and plays signicant neuroprotective roles in AD (Jia
etal., 2024). In addition, the dysregulation of the thioredoxin system
increases susceptibility to cell death, and changes in Trx and TrxR
levels are signicantly associated with the progression of AD (Qaiser
etal., 2024).
Research on neurodegenerative, neuroinammatory, and neuro-
oxidative stress in related brain diseases revealed that genetic and
environmental factors aect Trx function and that the Trx system may
be an important target for disease intervention and treatment
(Bjørklund etal., 2022). Glutaredoxin (Grx) 1 regulates redox signal
transduction and protein redox homeostasis by catalyzing reversible
s-glutathione modication, thereby exerting neuronal eects
(Gorelenkova and Mieyal, 2019). erefore, controlling oxidative
TABLE1 Disulfidptosis-related genes in the CNS.
Disease Disulfidptosis-related genes
Neurogliomas SLC3A2, NDUFA11, 0XSM, NUBP1,
LRPPRC, RPN1, GYSI
Alzheimer’s disease SLC7A11, SLC3A2, GYSI, OXSM, NUBPL,
NDUFA11, NCKAP1, LRPPRC
Ischemia stroke SLC2A3, SLC2A14, SLC7A11, NCKAP1

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stress responses and maintaining redox balance through the Trx and
Grx systems are highly important for the prevention and treatment of
Alzheimer’s disease, which prompted us to further explore the
correlation between disulde cell death and these processes.
4.1.2 Parkinson’s disease
Parkinson’s disease is also a prevalent neurodegenerative disease
characterized by a progressive decrease in neurological function
(Bloem et al., 2021). A previous study revealed that signicant
alterations in the distribution of antioxidant enzymes and high levels
of free radicals play important roles in the development of Parkinson’s
disease (Li etal., 2022). e accumulation of ROS leads to nigrostriatal
neuronal death in PD (Trist etal., 2019). Additionally, dynamic thiol-
disulde homeostasis is disrupted in patients with Parkinson’s disease
(Vural etal., 2017). e expression of the Parkinson’s disease-related
gene Parkin contributes to the network of sulydryl groups available
in the cell, including glutathionylation, which involves reversible post-
translational modications of selected cysteine residues (El et al.,
2023). Moreover, a cluster analysis of S-glutathionylated targets, which
are known to play a role in apoptosis and inammation according to
the Gene Ontology (GO) collection or Kyoto Encyclopedia of Genes
and Genomes (KEGG), revealed a putative overlapping association
between Grx1 and neurodegenerative diseases (Gorelenkova and
Mieyal, 2019). Higher amounts of TRX and GRX were found to
protect cells from the reactive dopamine metabolite 6-OHDA-
benzenediol, which is critical for neuronal survival in dopamine-
induced cell death (Arodin etal., 2014). Bioinformatics analysis and
invitro and invivo experiments have shown that the abnormal balance
of thiol/disulde bonds leading to oxidative stress is the pathological
mechanism underlying neuronal damage in neurodegenerative
diseases. erefore, further investigation of its association with
disuldptosis is highly important.
4.2 Neurogliomas
Neurogliomas are the predominant malignant tumors that
originate in the CNS (Ostrom etal., 2023). Recently, the disuldptosis
related genes (DRGs) SLC3A2, NDUFA11, OXSM, NUBPL, LRPPRC,
RPN1, and GYS1 were found to besignicantly associated with glioma
cells. e upregulation of the disuldptosis-related gene SLC3A2
inuences immune cell inltration in gliomas, notably macrophage
inltration, and impacts tumor migration and invasion, consequently
aecting the tumor microenvironment (Xu Y. et al., 2024).
Additionally, a study revealed that high expression of LRPPRC was
positively correlated with a favorable prognosis for gliomas, but
increased expression of RPN1 and GYS1 was associated with an
unfavorable prognosis (Guo etal., 2023). Additionally, thioredoxin
NADPH reductase (TrxR) plays a crucial role in the progression of
malignancies (Branco etal., 2020). e redox function of thioredoxin
is largely dependent on TrxR, with NADPH serving as an electron
donor (Saccoccia etal., 2014). SLC7A11 was identied as the gene that
is most signicantly associated with disuldptosis in tumors (Huang
etal., 2023; Xu B. etal., 2024). SLC7A11 expression in gliomas plays a
signicant role in tumorigenesis, tumor progression, and resistance to
conventional chemotherapy. Several studies have shown that glioma
cells upregulate the expression of SLC7A11, which regulates
glutathione production and glioma growth (Polewski etal., 2016).
Nrf2 is a transcription factor that is sensitive to redox changes and
capable of regulating the expression of the intracellular redox balance
proteins GPX4 and SLC7A11in glioma cells (Gao et al., 2020).
Chrysomycin A (Chr-A) further altered the levels of nicotinamide
adenine dinucleotide phosphate (NADPH), leading to oxidative stress
and downregulation of Nrf-2 to inhibit glioblastoma (Liu D. N. etal.,
2024). e upregulation of disuldptosis related genes SLC3A2 and
SLC7A11 promotes the occurrence and progression of glioma tumors,
therefore, a signal target of disuldptosis may be used in the
therapeutic schedule for neurogliomas.
4.3 Ischemic stroke
4.3.1 Factors associated with disulfidptosis in
stroke patients: glucose starvation and SLC7A11
Stroke includes both ischemic and hemorrhagic stroke; both lead
to abnormal cerebral blood ow and disrupt the delivery of oxygen
and glucose, resulting in cellular dysfunction, such as mitochondrial
oxidative phosphorylation and bioenergetic stress (An etal., 2021;
Zheng J. etal., 2018). In ischemic stroke, blood vessel blockage results
in glucose and oxygen deciency, which triggers several biological
response pathways and ultimately leads to irreversible brain damage
(Sharma etal., 2022). Trx/TrxR is an NADPH-dependent cellular thiol
reduction-antioxidant system, and the PPP and glucose oxidative
decomposition are the main sources of NADPH (Wang etal., 2022).
Reduced coenzyme II (NADPH) is the reduced form of NADP+ and
is derived mainly from the pentose phosphate pathway (PPP) of
glucose oxidative degradation, and NADPH depletion is also
associated with ischemic stroke (Zhang and Peng, 2014). Clinical
studies have proposed that changes in TyG-BMI, calculated via the
formula [triglyceride (mg/dL) × fasting blood glucose (mg/
dL)/2] BMI (kg/m2), are associated with the prognosis of stroke (Huo
etal., 2023; Yang etal., 2023). us, glucose starvation, which is an
initial factor necessary for disuldptosis, occurs in cerebral ischemia.
Recently, dierential gene expression analysis revealed that four DRGs
(SLC2A3, SLC2A14, SLC7A11, and NCKAP1) are associated with
stroke (Liu S. P. etal., 2024). Single cell analysis shows that the seven
types of DRGs (ACTB, IQGAP1, FLNA, PDLIM1, MYH10, INF2 and
SLC7A11) are mainly distributed in the immune cell types of ischemic
stroke (Qin et al., 2023). Recent studies have found that SLC7A11
expression inhibits M1 polarization in microglia while promoting M2
polarization in OGD models (Zhao etal., 2024). A study revealed that
increased SLC7A11 expression helps enhance GSH synthesis, which
increases resistance to oxidative damage and prevents neuronal
ferroptosis during cerebral ischemia (Li etal., 2023; Yuan etal., 2021).
erefore, SLC7A11, a subunit of the Xc system that imports cystine
through the export of glutamate at a 1:1 ratio, may beinvolved in the
crosstalk between ferroptosis and disuldptosis in ischemic stroke.
Studies have shown the protective eects of Peroxiredoxin 1 (PRDX1)
on stroke through disuldptosis and the ischemic postconditioning’s
(IPostC) mechanism. is marks an important step forward in stroke
research and potential treatment development (Liu S. etal., 2024). A
precursor of cysteine, known as L-2-oxothiazolidine-4-carboxylic acid
(OTC), decreases neurobehavioral performance in stroke models (Liu
Y. et al., 2020). Empirical clinical data have demonstrated that
individuals exhibit considerably increased serum concentrations of
homocysteine and cysteine in the acute phase of atherothrombotic

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stroke (Salemi etal., 2009). A study reported that cysteine levels can
increase 10–13-fold over 8 h in the ischemic hippocampus and
striatum, which are derived largely from GSH (Slivka and Cohen,
1993). e accumulation of cysteine, which originates from GSH,
substantially increased excitotoxic damage and disrupted the balance
of GSH/GSSG tissue damage caused by stroke in a rat model (Qu
etal., 2006).
4.3.2 Disulfidptosis-associated redox state: thiol/
disulfide bond regulation in stroke
Disuldptosis is a method of cell death that involves a reduction–
oxidation (redox) reaction and the production of disulde bonds
(Wang etal., 2023). Moreover, preliminary research has indicated that
alterations in thiol levels during oxidative stress may beassociated
with the size of the infarct resulting from ischemic stroke. Additionally,
reversing thiol deciency and restoring the thiol-disulde balance that
reduce disulde accumulation and inhibit oxidative damage, which
can impede the damage caused by ischemic stroke (Bektas et al.,
2016). Trx/TrxR is an NADPH-dependent cellular thiol reduction
antioxidant system associated with disulde stress. NADPH originates
from the PPP, in which the oxidative decomposition of glucose is
aected by hypoxia (Wang etal., 2022). e Trx system is crucial for
regulating apoptosis, redox status, and antioxidant defenses
(Matsuzawa, 2017). erefore, Trx may have a neuroprotective
function in individuals suering from acute ischemic stroke, and
serum Trx levels are novel diagnostic and prognostic indicators that
are also closely related to the severity of intracranial hemorrhage and
long-term mortality. Additionally, the overexpression of Grx1
decreases the level of S-glutathionylation, reduces the depletion of
GSH and the formation of disulde bonds, and suppresses neuron
damage during focal ischemia (Takagi etal., 1999).
4.3.3 Disulfidptosis-associated signaling pathway:
Nrf2/Trx regulation in stroke
Nuclear factor E2-associated factor 2 (Nrf2) is a transcription
factor that binds to Kelch-like ECH-associated protein 1 (KEAP1)
(Suzuki etal., 2023). In the nucleus, they function along with other
coactivators to initiate the transcription of target genes under
certain stimuli, such as oxidative stress, disrupting binding (Baird
and Yamamoto, 2020). e Keap1-Nrf2 system is a sulydryl-based
sensor-eect device that maintains redox homeostasis and is vital
to cellular defense against exogenous and endogenous oxidative and
electrophilic stress (Yamamoto etal., 2018). Endogenous Nrf2 is
activated aer ischemic stroke, resulting in an initial increase in the
expression of overall Nrf2 protein and a subsequent decrease in the
ischemic zone (Tian etal., 2020; Yang etal., 2009). Oxygen–glucose
deprivation/reperfusion (OGD/R)-induced ferroptosis can
bereversed by accelerating the transcription of GPX4 via the Nrf2-
SLC7A11 signaling pathway (Liu et al., 2023b), which may
beassociated with disuldptosis. Aer transient middle cerebral
artery occlusion in Nrf2 gene knockout mice, the induction and
activation of antioxidant enzymes are inhibited, resulting in a larger
stroke area (Zhang etal., 2017). A study revealed that Nrf2 siRNA
injection decreases the protein and mRNA expression of Trx1in
middle cerebral artery occlusion (MCAO) model rats; therefore,
Trx1 is regulated by Nrf2, which has a neuroprotective function (Li
et al., 2015). Under ischemic conditions, Nrf2 can regulate the
disuldptosis-related proteins SLC7A11 and the Trx system.
erefore, whether Nrf2 is a regulatory target of disuldptosis aer
cerebral ischemia deserves further investigation. Further
investigations are needed to determine which of these factors are
important target signals of disuldptosis and whether a temporal
sequential relationship exists between the occurrence of
disuldptosis and ferroptosis in stroke. ese studies suggest that
an imbalance in thiol/disulde redox reactions during disuldptosis
might constitute a novel pathogenic pathway of stroke or other
disorders of the CNS; deeper insights into the mechanism
underlying disuldptosis may provide new targets and new
treatments for CNS diseases.
5 Implications of disulfidptosis
treatment
Research on the pathogenesis and treatment of disuldptosis is
still in the early stage and has focused mainly on various types of
cancer. A review of the literature on drug intervention for disuldptosis
target genes and signaling pathways may provide new directions for
research on CNS therapy. N-acetylcysteine (NAC) have antioxidant,
anti-inammatory, and neuroprotective processes in the CNS (Santos
etal., 2017). One study suggested that NAC acts as an antioxidant to
increase the intracellular concentration of GSH, which is the critical
biological thiol responsible for maintaining the cellular redox balance
(Tenório etal., 2021). NAC promotes the regeneration of free thiols
through disulde exchange, preventing the accumulation of cystine or
other disuldes under glucose starvation (e.g.,
Cys-Cys + NAC → Cys + NAC-Cys) (Sarıtaş etal., 2024). In recent
clinical trials on acute ischemic stroke, it has been found that
intravenous injection of N-acetylcysteine can enhance the safety and
ecacy of recombinant tissue plasminogen activator (rtPA or
alteplase) adjuvant therapy (Zhao etal., 2017). In summary, in the
carrier experiment, NAC can increase GSH and reduce the
accumulation of cystine and disulde. Webelieve that NAC may have
a therapeutic eect on inhibiting neuronal disuldptosis aer
CNSD. Lipoic acid (α-LA), also known as thioctic acid, includes a
reduced (dihydro-lipoic acid, DHLA) form, which exerts its
neuroprotective eect on neurodegenerative disorders by inhibiting
the formation of oxidizing material and promoting neurotransmitters
(Santos etal., 2017). Liraglutide (LIRA), a glucagon-like peptide-1
(GLP-1) analog widely used in clinical applications, enhances the
expression of Trx, Nrf2, and p-Erk1/2 to establish a protective eect
against neurodegenerative diseases (Liu J. etal., 2020). Salidroside
(Sald), a traditional Chinese medicine, may suppress oxidative stress
by inducing Trx and peroxiredoxin-I (PrxI) in neuroblastoma (Zhang
etal., 2010). Ebselen, a synthetic organoselenium compound, protects
neurons from damage caused by free radicals by interacting with
thiols, peroxynitrites, and hydroperoxides (Wang J. etal., 2020). e
antioxidant Dl-3-n-butylphthalide can hinder the NLRP3
inammasome and decrease the severity of AD-like symptoms by
aecting the Nrf2-TXNIP-TrX pathway (Wang et al., 2019).
Disuldptosis may be an important pathological mechanism in
neurodegenerative diseases. In response to the imbalance of
intracellular sulfur metabolism, thiol and disulde balance, as well as
the systemic regulation of Trx and Grx and the cross-talk between cell
death aer the occurrence of the disease, eective interventions and
treatment drugs have been explored to identify pathways and multiple

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approaches for treating neurodegenerative diseases. Disuldptosis is
a novel mode of programmed cell death, and the investigation and
intervention of pathological mechanisms may reveal various eective
targets. is information can beused to treat associated CNS diseases
eectively (Table2).
6 Outlook and conclusions
In this review, weemphasized that NADPH metabolism, high
SLC7A11 expression, and the cystine/cysteine balance are
important metabolic features of disulfidptosis. By describing the
endogenous and exogenous elements involved in novel cell death
disulfidptosis and identifying associations between disulfidptosis
and CNS disorders, such as neurodegenerative diseases, gliomas,
and ischemic stroke, this review summarizes disulfidptosis-
related genes involved in neurodegenerative diseases, gliomas,
and ischemic strokes and discusses how disulfide stress and redox
imbalance contribute to the onset and progression of CNSD. The
Trx and Grx systems, which play antioxidant defense roles during
disulfide stress, are involved in neurological diseases. In the
future, wecan use bioinformatics analysis and invitro and invivo
experiments to detect target genes and protein proteins associated
with disulfidptosis in neurological diseases to search for clinical
biomarkers for treatment. Wesuggest that disulfidptosis might
be a crucial novel pathological mechanism underlying CNS
diseases. Moreover, some similarities between disulfidptosis and
ferroptosis/cuproptosis may reveal new insights into the
pathogenesis of CNS diseases and help develop more
comprehensive therapeutic strategies. Therefore, it is necessary
to conduct a thorough analysis of other pathways involved in
mediating disulfidptosis.
However, the potential mechanism of disuldptosis still needs
further exploration, and this innovative approach will provide a basis
to overcome future challenges. Will disuldptosis only occur in the
actin cytoskeleton, and are other proteins sensitive to disulde stress?
What are the dierences between disulde bonds and other protein
post-translational modications, especially with regard to
glutathionylation? In future basic and clinical research, can weselect
appropriate therapeutic drugs for patients with central nervous system
diseases based on their susceptibility to disuldptosis? Exploring the
mechanism underlying disuldptosis and its contribution to various
central nervous system diseases has crucial theoretical and practical
value for identifying eective treatment strategies.
Author contributions
JC: Writing– original dra. DL: Writing– review & editing. YX:
Writing – review & editing. BT: Writing– review & editing. JD:
Writing – review & editing. ZM: Writing– review & editing. JL:
Resources, Writing– original dra.
Funding
e author(s) declare nancial support was received for the
research, authorship, and/or publication of this article. is study was
supported by National Natural Science Foundation of China
(81774033) and Natural Science Foundation of Hunan Province
(2025JJ90019).
Conflict of interest
e authors declare that the research was conducted in the
absence of any commercial or nancial relationships that could
beconstrued as a potential conict of interest.
Generative AI statement
e authors declare that no Gen AI was used in the creation of
this manuscript.
Publisher’s note
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their aliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may beevaluated in this article, or
claim that may bemade by its manufacturer, is not guaranteed or
endorsed by the publisher.
TABLE2 Disulfidptosis-related therapeutic drugs.
Medicine Source Mechanism
of action
Corresponding
disease
NAC ermal
compound
Increase
concentration of
GSH
CNS
Lipoic acid Organic
compounds
Inhibits the
formation of
oxides and
promotes
neurotransmitters
Neuroelegenerative
disease
LIRA Synthetic
acylated
GIP-1
analogs
Enhanced
expression of Trx,
Nrf2, P-Erk1/2
Neuroelegenerative
disease
Salidroside Botany Trx Prx-1 Neuroblastoma
Ebselen Organic
chemicals
iols,
peroxynitries
hydroperoxides
Neuroelegenrative
disease
Dl-3-n-
butylphthalide
Apium
graveolens
Linn
NLRP3 Alzheimer’s disease

Chang et al. 10.3389/fnins.2025.1514253
Frontiers in Neuroscience 12 frontiersin.org
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