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Citation: Xu, Y.; Jia, B.; Li, J.; Li, Q.;
Luo, C. The Interplay between
Ferroptosis and Neuroinflammation
in Central Neurological Disorders.
Antioxidants 2024,13, 395. https://
doi.org/10.3390/antiox13040395
Academic Editor: Pamela A. Maher
Received: 11 March 2024
Revised: 23 March 2024
Accepted: 25 March 2024
Published: 26 March 2024
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
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antioxidants
Review
The Interplay between Ferroptosis and Neuroinflammation in
Central Neurological Disorders
Yejia Xu 1,2,† , Bowen Jia 1,†, Jing Li 1, Qianqian Li 3 ,4, * and Chengliang Luo 1,2,3,*
1Department of Forensic Medicine, School of Basic Medicine and Biological Sciences, Soochow University,
Suzhou 215123, China
2Hebei Key Laboratory of Forensic Medicine, College of Forensic Medicine, Hebei Medical University,
Shijiazhuang 050017, China
3NHC Key Laboratory of Drug Addiction Medicine, Department of Forensic Medicine, School of Forensic
Medicine, Kunming Medical University, Kunming 650500, China
4School of Forensic Medicine, Wannan Medical College, Wuhu 241002, China
*Correspondence: bzliqian@126.com (Q.L.); clluo@suda.edu.cn (C.L.)
†These authors contributed equally to this work.
Abstract: Central neurological disorders are significant contributors to morbidity, mortality, and long-
term disability globally in modern society. These encompass neurodegenerative diseases, ischemic
brain diseases, traumatic brain injury, epilepsy, depression, and more. The involved pathogenesis is
notably intricate and diverse. Ferroptosis and neuroinflammation play pivotal roles in elucidating
the causes of cognitive impairment stemming from these diseases. Given the concurrent occurrence
of ferroptosis and neuroinflammation due to metabolic shifts such as iron and ROS, as well as their
critical roles in central nervous disorders, the investigation into the co-regulatory mechanism of
ferroptosis and neuroinflammation has emerged as a prominent area of research. This paper delves
into the mechanisms of ferroptosis and neuroinflammation in central nervous disorders, along with
their interrelationship. It specifically emphasizes the core molecules within the shared pathways
governing ferroptosis and neuroinflammation, including SIRT1, Nrf2, NF-
κ
B, Cox-2, iNOS/NO
·
,
and how different immune cells and structures contribute to cognitive dysfunction through these
mechanisms. Researchers’ findings suggest that ferroptosis and neuroinflammation mutually promote
each other and may represent key factors in the progression of central neurological disorders. A
deeper comprehension of the common pathway between cellular ferroptosis and neuroinflammation
holds promise for improving symptoms and prognosis related to central neurological disorders.
Keywords: ferroptosis; neuroinflammation; central neurological disorders; blood–brain barrier
1. Introduction
Nerve cell death stands as a significant contributor to neurological disorders, diseases,
and injuries. The unexpected or programmed demise of neurons and glial cells across
various regions of the nervous system disrupts sensory, motor, cognitive, learning, and
memory functions [
1
–
3
]. Ferroptosis, a form of regulated cell death triggered by iron
overload, involves distinct inducible factors and metabolites [
4
]. Since its inception in
2012, research has revealed that cellular ferroptosis can occur ubiquitously throughout the
human body, including within the nervous system. Imbalances in iron metabolism prompt
nerve cells to generate high levels of reactive oxygen species via the Fenton reaction, lead-
ing to lipid peroxidation and impairment of cellular REDOX functions [
5
]. Furthermore,
ferroptosis-induced mitochondrial atrophy and functional decline impede the energy sup-
ply to neurons, disrupting electrical and chemical signal transmission [
6
]. The ferroptosis of
nerve cells within the central nervous system undermines cellular physiological functions,
with cognitive impairment emerging as a hallmark mechanism in central nervous system
diseases and injuries.
Antioxidants 2024,13, 395. https://doi.org/10.3390/antiox13040395 https://www.mdpi.com/journal/antioxidants
Antioxidants 2024,13, 395 2 of 31
Neuroinflammation represents a unique inflammatory response within the human
body, serving as the central nervous system’s defense mechanism against diverse stimuli [
7
].
This process involves the activation of microglia and astrocytes, the primary immune-active
cells, which release various cytokines and chemokines [
8
,
9
]. In the context of central
nervous system diseases and injuries, neuroinflammation is a common occurrence, leading
to the release of numerous effector proteins that disrupt neuronal excitability, thereby
exacerbating nerve function impairment [10].
The coexistence of neuroinflammation and cell ferroptosis in neuropathy has sparked
significant interest in recent years within the study of central nervous system diseases.
Common inflammatory factors released during neuroinflammation exhibit close associ-
ations with proteins that govern cellular iron metabolism and lipid metabolism [
11
]. In
light of this, researchers are delving into the potential links and shared pathways between
neuroinflammation and ferroptosis by uncovering the molecular mechanisms that underlie
diverse structural alterations within cells following central nervous system diseases and
injuries.
2. Ferroptosis and Central Neurological Disorders
2.1. Mechanism and Pathway of Ferroptosis
Ferroptosis is a newly discovered type of programmed cell death, first identified in
2012 by Drs. Brent R. Stockwell, Scott Dixon, and their research team [
4
]. It is considered an
independent mechanism of cell death because cells undergoing ferroptosis exhibit distinct
morphological, compositional, and metabolic characteristics compared to common forms
of cell death, such as apoptosis and necrosis. Morphologically, cells undergoing ferroptosis
do not display fragmented or shrunken nuclei but instead exhibit atrophied mitochondria
and a reduced number of cristae [
12
]. In the cytoplasmic component, the levels of free iron
and reactive oxygen species are elevated in these cells [13].
The cellular metabolism involved in ferroptosis encompasses various facets, including
abnormalities in iron homeostasis, lipid metabolism, and glutathione-related metabolic
changes [
4
]. These alterations in metabolism often serve as critical targets for the regulation
of ferroptosis. Pertaining to iron metabolism, cells undergoing ferroptosis exhibit modifica-
tions in the processes of iron uptake, storage, utilization, and efflux, culminating in cellular
iron overload [
14
,
15
]. Researchers have addressed the issue of elevated cellular iron levels
by regulating proteins such as transferrin receptor, ferritin, ferroportin1, and employing
iron chelators like deferriamine [
14
,
16
,
17
]. In the realm of cellular lipid metabolism, the
peroxidation of polyunsaturated fatty acids into PUFA-PLs represents a pivotal pathway
in ferroptosis [
4
]. Building upon this foundation, strategies such as inhibiting PUFAacyl-
CoA derivatives (PUFA-CoAs) and ACSL4, a key enzyme generated by lipoxygenase,
or promoting monounsaturated fatty acids (MUFAs) over PUFAs have been explored as
means to impede ferroptosis [
18
–
20
]. Concerning intracellular REDOX metabolism, diverse
antioxidant pathways have been identified as capable of combating the progression of
cellular ferroptosis. Apart from the well-known GPX4 classical pathway, recent discoveries
have unveiled the potential of pathways like FSP1/CoQ10, DHODH, and GCH1/BH4 in in-
hibiting intracellular peroxidation by reducing CoQ10 at the plasma membrane, converting
CoQ to panthenol, and sequestering free radicals, respectively [
21
–
23
]. Ongoing research
continues to enhance our understanding of the mechanisms and regulation of ferroptosis,
while investigations into its interplay with other cell death mechanisms and additional
metal elements such as copper and zinc offer novel avenues for exploration [24].
2.2. Ferroptosis in Central Neurological Disorders
The typical progression of ferroptosis has been discovered in various systemic diseases.
Over the past decade, researchers have discovered that ferroptosis plays a crucial role in
many central nervous system diseases and injuries, including neurodegenerative diseases,
stroke, epilepsy, brain injury, and depression. In the early stages of research, significant
iron content and elevated transferrin levels were observed in the local blood vessels and
Antioxidants 2024,13, 395 3 of 31
brain parenchyma of ischemic stroke [
25
]. With the recognition of ferroptosis, studies
have found that ischemic stroke regulation of ACSL4 can change the pathologic severity
through the pathway of ferroptosis [
26
]. Alzheimer’s disease is characterized by the
deposition of
β
-amyloid protein (A
β
) plaques and neurofibrillary tangles (NFTs) in the
brain, which are key pathological features. There is evidence suggesting that ferroptosis
in the Alzheimer’s disease (AD) brain exhibits a unique manifestation: the abnormal
elevation of xCT exacerbates neuroexcitatory toxicity and amyloid-beta (A
β
) accumulation,
ultimately impairing the neural function in individuals with AD [
27
]. Parkinson’s disease
is marked by symptoms such as resting tremors resulting from the degeneration of neurons
in the substantia nigra of the midbrain. Research indicates that dopamine in the brain could
potentially have a positive regulatory effect on GPX4. Therefore, the depletion of dopamine
in the brain of individuals with Parkinson’s disease (PD) may lead to ferroptosis due to the
loss of GPX4 [
28
]. Furthermore, in epileptic brains, astrocytes modulate xCT/GSH/GPX4
via chemokines, leading to neuronal ferroptosis, possibly associated with synchronous
brain firing processes [
29
]. Traumatic brain injury (TBI) is a major cause of death and
disability in developed countries. The expression of TFR, FPN, and GPX4 exhibited varying
degrees of increase at 6 h, 1 day, 3 days, 7 days, and 3 weeks in the brain tissue of the injured
area. Additionally, it has been observed that ferroptosis-specific inhibitors can effectively
inhibit the extent of secondary damage following TBI [30].
The discovery of the various diseases mentioned above highlights that dysregulation
of iron metabolism, lipid metabolism, and abnormalities in GPX4-related pathways in the
affected areas have become common features of brain neurological diseases. Ferroptosis
plays a significant role in the pathogenesis of central nervous system diseases, and inter-
ventions targeting ferroptosis have become crucial strategies for combating these diseases.
By focusing on modulating ferroptosis and related pathways, researchers aim to develop
novel therapeutic approaches to address the underlying mechanisms of these neurological
disorders and potentially improve patient outcomes.
2.3. Cognitive Dysfunction Caused by Ferroptosis
The cognitive function of mammals relies on the integrity of structures such as the
cerebral cortex, hippocampus, and basal ganglia. Cognitive dysfunction is a primary
symptom of central nervous system diseases and serves as a key indicator for assessing
therapeutic effects and evaluating prognosis in numerous conditions. Neuronal damage in
various brain regions stands as the fundamental cause of cognitive impairment. Prior to
the definition of ferroptosis, numerous studies had revealed a distinct spatial and temporal
correlation between iron overload and cognitive dysfunction in the brain [
31
]. In addition
to discovering in mouse models that a high-iron diet during the neonatal period led to
cognitive impairment in adulthood, researchers also observed that iron overload in various
regions of the human brain worsened cognitive dysfunction in neurological diseases [
32
].
The inhibition of elevated iron levels in certain neurodegenerative disease models through
iron chelators has proven effective in reducing cognitive impairment [31].
In recent years, ferroptosis has been identified as prevalent in a range of central nervous
system diseases, causing damage to nerve cells and ultimately leading to neuronal death
and cognitive dysfunction. Mei and Liu’s research team illustrated that Nrf2-dependent
cortical neuronal ferroptosis induces severe cognitive impairment in mice, as evidenced by
Morris water maze tests, Rasin scores, and electroencephalograms of epileptic mice [
33
].
Studies have indicated a positive correlation between the extent of cognitive impairment
resulting from traumatic brain injury, sepsis-associated epilepsy, and epilepsy and the
degree of ferroptosis in hippocampal neurons [
34
–
36
]. Parkinson’s disease stems from
the ferroptosis of neurons in the substantia nigra compacta (SNpc), leading to motor
dysfunction like static tremors, as well as subcortical cognitive deficits such as executive
dysfunction and attention deficit [
37
]. The inhibition of ferroptosis to ameliorate cognitive
impairment in central nervous system diseases represents a current focal point in the
treatment of diverse conditions.
Antioxidants 2024,13, 395 4 of 31
3. Neuroinflammation in Central Neurological Disorders
Neuroinflammation is essentially an immune response triggered by physiological
abnormalities or pathological conditions of the central nervous system. It is observed
in nearly all cases of central nervous dysfunction, including aging, infectious brain dis-
eases, autoimmune encephalopathy, neurodegenerative diseases, ischemic stroke, and
brain injury [
38
–
43
]. The primary effector cell phenotypes of neuroinflammation are two
centrally located innate immune cells: microglia and astrocytes [
44
]. Furthermore, when
the structure and function of the blood–brain barrier, the centerpiece of immune privilege in
defending the brain, is compromised, peripheral immune cells (such as neutrophils, mono-
cytes/macrophages, lymphocytes, etc.) invade the brain and contribute to the amplification
of neuroinflammation [45].
The initiation of neuroinflammation is typically accompanied by the injury of en-
dogenous nerve cells or the invasion of exogenous infectious agents and toxins. Similar
to immune processes in other systems, damaged or dead cells and invading infectious
agents in the brain release damage-associated molecular patterns (DAMPs) and pathogen-
associated molecular patterns (PAMPs), respectively [
46
,
47
]. Microglia and astrocytes
in the brain are activated by receptors to become reactive microglia and reactive astro-
cytes [
48
,
49
]. These activated innate immune cells secrete a variety of cytokines in response
to specific phenotypic changes, including interleukins, interferons, tumor necrosis factors,
chemokines, and reactive oxygen species, which contribute to the amplification of neu-
roinflammation [50]. When pro-inflammatory cytokines take precedence, they trigger cell
death, affecting neurons, glial cells, and endothelial cells. Destruction of the endothelial
cells of the blood–brain barrier leads to the invasion of peripheral immune cells into the
brain at different stages of the disease [
51
]. These infiltrating peripheral cells further disrupt
the integrity of the brain structure, harm neurons, and worsen the organic brain damage
caused by neuroinflammation [52].
Neuroinflammation causes damage to neurons in the affected region, including axonal
degeneration, abnormal energy metabolism, destruction of synaptic structures, and even
neuronal death [
44
]. Additionally, under pathological conditions, astrocytes and microglia
lose their original physiological functions, such as neurotrophic function and maintenance
of synaptic plasticity [
53
]. The reduced level of brain-derived neurotrophic factor (BDNF)
in the brain inhibits the repair of neural synapses [
54
]. These consequences lead to the dis-
ruption of nerve impulse transmission, ultimately resulting in impaired cognitive function
and a series of brain functional abnormalities.
4. The Link between Neuroinflammation and Ferroptosis
Recent studies focusing on the brain and spinal cord have illuminated the intercon-
nected nature of cell ferroptosis and neuroinflammation in the realm of nerve injury and
degeneration. Intracellular oxidative stress stemming from metabolic irregularities dur-
ing ferroptosis, coupled with disruptions in mitochondrial structure and function, can
exacerbate neuroinflammation [
55
–
57
]. The altered phenotypes of immune cells during
inflammation and the release of pro-inflammatory factors can trigger ferroptosis in both
immune cells themselves and neighboring neurons [
58
]. Thus, exploring the shared molec-
ular communication processes between cellular ferroptosis and neuroinflammation offers
valuable insights into the pathogenesis of diverse central nervous system disorders, identi-
fies potential therapeutic targets, and enhances the management of cognitive, sensory, and
motor symptoms associated with these conditions. This chapter delves into the converging
pathways of ferroptosis and neuroinflammation across various central nervous system
diseases, examining cell phenotypes, specific structures, and microscopic molecules to
unveil commonalities and potential treatment avenues.
Antioxidants 2024,13, 395 5 of 31
4.1. Molecular Mechanisms and Signaling Pathways
4.1.1. SIRT1
Silent information regulator 1 (SIRT1) is a class III histone deacetylase that is widely
expressed in mammals. Recent research has convincingly demonstrated its close associa-
tion with cellular energy metabolism, inflammation, and various programmed cell death
pathways. The biological activity of SIRT1 requires the presence of NAD+ and responds
to changes in energy status by regulating the intracellular NAD+/NADH ratio [
59
,
60
].
Due to its exceptional performance in the body’s defense mechanisms and death modes
such as oxidative stress, inflammation, apoptosis, and ferroptosis, the role of SIRT1 in the
pathological process of central nervous system disease and injury is worth inferring.
The expression of SIRT1 is intricately linked to AMP-activated protein kinase (AMPK).
Activation of AMPK can enhance SIRT1 activity in a NAD+-dependent manner, thereby
inhibiting downstream inflammatory pathways and ferroptosis pathways [
61
,
62
]. More-
over, SIRT1 has the ability to elevate AMPK levels through acetylation modification [
63
].
Consequently, the reciprocal activation and regulation of AMPK and SIRT1 may establish
a positive feedback loop within cells, serving as a mechanism for the body to counteract
physiological dysfunction. Additionally, both AMPK and SIRT1 possess the capability to
modulate gene expression by co-regulating the activity of transcription factors, including
the mitochondrial functional protein PGC-1
α
[
64
,
65
]. PGC-1
α
is likely a pivotal target
of SIRT1 due to its transcriptional regulation, with the associated transcription factors
encompassing PPARα, PPARγ, FoxO1, Nrf1, Nrf2, etc. [66–69].
Firstly, the mechanism by which SIRT1 repairs the damaged nervous system involves
the participation of Nrf2. Specifically, studies have indicated that following traumatic
brain injury, SIRT1 positively regulates Nrf2 concentration, inducing the expression of
Prxs (an ROS management system) and ultimately inhibiting p38 MAPK (Figure 1). This
modulation not only reduces acute neurotrauma after brain injury but also improves
cognitive function and long-term prognosis [
70
–
72
]. P38 is a serine/threonine protein
kinase that plays a crucial role in cell apoptosis/inflammatory response and the nervous
system [
73
,
74
]. Additionally, it has been demonstrated that two SIRT1 agonists, astaxanthin
and berberine, promote cognitive and memory recovery in mice through the SIRT1/p38
MAPK pathway [
70
,
75
]. Furthermore, the SIRT1/Nrf2 pathway mitigates ferroptosis after
brain injury by activating GPX4, a key factor in ferroptosis [
76
,
77
]. Upregulation of SIRT1
can reverse the decrease in GPX4 content in the hippocampus after ischemic hypoxic injury,
which is an important treatment target for HIBI [
76
]. Surprisingly, in some inflammatory
model diseases, intervention-induced activation of the SIRT1/Nrf2/GPX4 pathway has
been shown to alleviate inflammatory factors, suggesting a possible role of this pathway in
neuroinflammation [78–80].
Secondly, SIRT1 is also involved in a cascade relationship with the important human
tumor suppressor gene p53, impacting SLC7A11, which increases intracellular and ex-
tracellular glutamate and cystine exchange, indirectly influencing GPX4’s inhibition of
ferroptosis (Figure 1). Knocking out SIRT1 and using ferrostatin-1, a specific inhibitor of
ferroptosis, have demonstrated similar inhibitory effects in the LPS-induced ferroptosis
model [
81
]. Studies on the acetylation levels of SIRT1 and P53 K382 after Baicalein treatment
have shown opposite trends [
82
], indicating that upregulation of SIRT1 may enhance the
expression of SLC7A11 by inhibiting the p53 gene. In brain injury resulting from cerebral
ischemia-reperfusion, a type of RNA-binding protein called pumilio 2 has been found to
decrease the expression of SLC7A11 by inhibiting SIRT1, leading to neuroinflammation
and ferroptosis in I/R [
83
]. It can be inferred that the SIRT1/p53/SLC7A11/GPX4 pathway
may play a key role in inducing a series of ferroptosis and neuroinflammatory effects in the
pathological processes of certain central nervous system diseases (Figure 1). Notably, due
to the distinct role of p53 in the cell cycle, the involvement of p53 in ferroptosis directly
inhibited by GPX4 differs from ferroptosis directly inhibited by SLC7A11 [84,85].
Antioxidants 2024,13, 395 6 of 31
Antioxidants 2024, 13, x FOR PEER REVIEW 6 of 32
RNA-binding protein called pumilio 2 has been found to decrease the expression of SLC7A11
by inhibiting SIRT1, leading to neuroinflammation and ferroptosis in I/R [83]. It can be inferred
that the SIRT1/p53/SLC7A11/GPX4 pathway may play a key role in inducing a series of fer-
roptosis and neuroinflammatory effects in the pathological processes of certain central nerv-
ous system diseases (Figure 1). Notably, due to the distinct role of p53 in the cell cycle, the
involvement of p53 in ferroptosis directly inhibited by GPX4 differs from ferroptosis directly
inhibited by SLC7A11 [84,85].
Figure 1. A schematic summary of the link between inflammation and ferroptosis in nerve cells.
SIRT1, Nrf2, and NF-κB intricately regulate one another, thereby influencing the magnitude of neu-
roinflammation and ferroptosis. SIRT1 and AMPK mutually boost each other’s expression, has-
tening the dissociation of Nrf2 and Keap1 through the upregulation of PGC-1α. Subsequently, Nrf2
translocates into organelles and binds to ARE, thereby orchestrating the transcriptional regulation
of various genes. Nrf2 can impede NF-κB activity via multiple pathways including the Nrf2/HO-1
pathway, STING/TBK-1 pathway, and Prxs/P38MAPK pathway. NF-κB, a pivotal transcription fac-
tor in inflammation regulation, not only triggers the NLRP3 complex for proinflammatory cytokine
release but also suppresses SIRT1 expression. Furthermore, SIRT1 inhibits p53 gene expression, in-
directly thwarting cellular ferroptosis through the GPX4 pathway. By modulating Prxs and
Fth/FPN, Nrf2 governs cellular oxidative stress and labile iron pools, thereby suppressing ferropto-
sis. NF-κB also stimulates Cox-2 and iNOS production, influencing neuroinflammation and ferrop-
tosis occurrence by impacting iron/ROS levels and inflammatory cytokines. Abbreviations: AA, ar-
achidonic acid; AMPK, adenosine 5’-monophosphate (AMP)-activated protein kinase; ARE, antiox-
idant responseelement; FPN, ferroportin; Fth, ferritin heavy; GPX4, glutathione peroxidase 4; GSH,
glutathione; GSSG, oxidized glutathione; HMGB1, high mobility group protein B1; HO-1, heme ox-
ygenase 1; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MyD88, Myeloid Dif-
ferentiation Factor 88; NF-κB, nuclear factor-kappaB; Nrf2, nuclear factor erythroid-2-related factor
2; PGs, prostaglandins; PGC-1α, PPAR-γ Coactivator 1 alpha; ROS, reactive oxygen species; SIRT1,
silent information regulator 1; STING, stimulator of interferon genes; TBK-1, TANK-binding kinase
1; TLR4, Toll-like receptor 4. Solid arrows indicate facilitation of expression or relocation. Dashed
arrows suggest potential facilitation of expression but with unclear mechanisms. Inhibition arrows
signify suppression of expression. Dashed inhibition arrows indicate potential suppression of ex-
pression but with unclear mechanisms. This figure was created with BioRender.com.
Figure 1. A schematic summary of the link between inflammation and ferroptosis in nerve cells.
SIRT1, Nrf2, and NF-
κ
B intricately regulate one another, thereby influencing the magnitude of neu-
roinflammation and ferroptosis. SIRT1 and AMPK mutually boost each other’s expression, hastening
the dissociation of Nrf2 and Keap1 through the upregulation of PGC-1
α
. Subsequently, Nrf2 translo-
cates into organelles and binds to ARE, thereby orchestrating the transcriptional regulation of various
genes. Nrf2 can impede NF-
κ
B activity via multiple pathways including the Nrf2/HO-1 pathway,
STING/TBK-1 pathway, and Prxs/P38MAPK pathway. NF-
κ
B, a pivotal transcription factor in
inflammation regulation, not only triggers the NLRP3 complex for proinflammatory cytokine release
but also suppresses SIRT1 expression. Furthermore, SIRT1 inhibits p53 gene expression, indirectly
thwarting cellular ferroptosis through the GPX4 pathway. By modulating Prxs and Fth/FPN, Nrf2
governs cellular oxidative stress and labile iron pools, thereby suppressing ferroptosis. NF-
κ
B also
stimulates Cox-2 and iNOS production, influencing neuroinflammation and ferroptosis occurrence
by impacting iron/ROS levels and inflammatory cytokines. Abbreviations: AA, arachidonic acid;
AMPK, adenosine 5’-monophosphate (AMP)-activated protein kinase; ARE, antioxidant respon-
seelement; FPN, ferroportin; Fth, ferritin heavy; GPX4, glutathione peroxidase 4; GSH, glutathione;
GSSG, oxidized glutathione; HMGB1, high mobility group protein B1; HO-1, heme oxygenase 1;
LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MyD88, Myeloid Differentia-
tion Factor 88; NF-
κ
B, nuclear factor-kappaB; Nrf2, nuclear factor erythroid-2-related factor 2; PGs,
prostaglandins; PGC-1
α
, PPAR-
γ
Coactivator 1 alpha; ROS, reactive oxygen species; SIRT1, silent
information regulator 1; STING, stimulator of interferon genes; TBK-1, TANK-binding kinase 1; TLR4,
Toll-like receptor 4. Solid arrows indicate facilitation of expression or relocation. Dashed arrows
suggest potential facilitation of expression but with unclear mechanisms. Inhibition arrows signify
suppression of expression. Dashed inhibition arrows indicate potential suppression of expression but
with unclear mechanisms. This figure was created with BioRender.com.
Furthermore, SIRT1 has been found to inhibit ferroptosis in nerve cells through a non-
GPX4-dependent ferroptosis protection pathway. In experiments with HT22 cells
in vivo
and
in vitro
in Alzheimer’s mice, Jiatong Zhang and Wei Li’s team demonstrated that the
upregulation of SIRT1 in AD inhibits ferroptosis via the FSP1 axis [
86
]. Similar results
were observed in a study on subarachnoid hemorrhage [
87
]. Moreover, a test of methyl
Antioxidants 2024,13, 395 7 of 31
naphthoquinone-4 (MK-4) suggests that SIRT1 may also protect neurons from ferroptosis
in subarachnoid hemorrhage by increasing DHODH levels [88].
Finally, SIRT1 plays a crucial role in attenuating various neuroinflammatory cascades
by downregulating nuclear factor-
κ
B (NF-
κ
B), a central molecule in inflammation
(Figure 1)
.
The regulatory function of SIRT1 in inflammation can involve HMGB1 and Toll-like re-
ceptors (TLR4) [
89
]. In cases of brain injury, SIRT1 is involved in reducing NF-
κ
B levels
through the HMGB1/TLR4 pathway [
90
] and inhibiting the expression of NLRP3 inflamma-
somes [
61
]. The downstream inflammatory pathway associated with NF-
κ
B activation can
result in the upregulation of various pro-inflammatory factors and cell phenotype transfor-
mations, such as microglia and astrocyte activation [
59
], M1 polarization of microglia [
91
],
and an increase in TNF-
α
, IL-1
β
, IL-6, and other inflammatory mediators [
59
,
91
]. Numer-
ous biomolecules activated by SIRT1 work to reduce NF-
κ
B expression, thereby helping to
alleviate neuroinflammation in the brain [59,60,89,92].
It is evident that the activation of silent information regulator 1 can trigger both
ferroptosis and inflammation in cells, usually through upstream regulatory means. As such,
upregulation of SIRT1 has emerged as a potential therapeutic target for the treatment of
neurological disorders and cognitive impairment in the brain. Resveratrol, a classic SIRT1
activator, has been widely used to reduce inflammation and cell death in diseases
[89,93–95]
.
However, there is still much to learn about the mechanism by which SIRT1 regulates
ferroptosis in nerve cells and inhibits the release of pro-inflammatory factors. For instance,
the specific intermolecular processes by which SIRT1 regulates FSP1 and DHODH are not
yet fully understood and disease models targeting these two atypical ferroptosis defense
mechanisms are limited. Furthermore, the SIRT1/p53 pathway has different direct effects
on GPX4 and SLC7A11, and the feedback relationship between p53, GPX4, and SLC7A11
requires further investigation.
4.1.2. Nrf2
The nuclear factor erythroid 2-related factor 2 (Nrf2) is a DNA-binding protein that
has its origins in the study of red blood cell production. While initial research on Nrf2
focused on its involvement in regulating globin gene expression, subsequent studies
have highlighted its crucial role in combating oxidative stress [
96
]. Nrf2 accomplishes
this by activating a variety of genes through binding to antioxidant response elements
(AREs), particularly promoting the expression of heme oxygenase-1 (HO-1) (Figure 1). This
activation of downstream pathways leads to an enhanced antioxidant response in different
types of cells.
The regulation of Nrf2 activity encompasses keap1-dependent and keap1-independent
pathways, with the keap1-Cul3-Rbx1 pathway playing a pivotal role. Upon exposure
to oxidative stress, the dissociation of keap1 from Nrf2 results in enhanced stability of
Nrf2 and its subsequent translocation into the nucleus to bind ARE [
96
]. In the context of
cerebral ischemia-reperfusion injury, the NLRP3 inflammasome can trigger downstream
antioxidant responses and influence ferroptosis by upregulating Nrf2 induced by keap1 as
a defensive reflex (Figure 1).
There are two primary forms of keap1-independent regulation. The first is the
PI3K/Akt-dependent pathway, which is activated in response to oxidative stress [
97
]. In
mouse HT22 cells, blocking the PI3K/Akt pathway hinders the antioxidant effect induced
by Nrf2, ultimately exacerbating neuroinflammation [
98
]. In cases of traumatic brain injury
(TBI), activation of the TrkB receptor upregulates Nrf2 through the PI3K/Akt pathway,
thereby reducing ferroptosis and TBI-related neuroinflammation. This process also partially
restores neurocognitive impairment. Consequently, the TrkB activator NAS has emerged as
an effective therapeutic target [
99
]. The second type involves the Hrd1-dependent path-
way, where Hrd1 binds to Nrf2, leading to its ubiquitination and subsequent degradation.
Consequently, this inhibits the cellular protective response [100].
Nrf2, upon translocating into the nucleus, plays a crucial role in the regulation of
more than 250 genes by binding to their specific sites. These genes are involved in various
Antioxidants 2024,13, 395 8 of 31
cellular processes such as oxidative stress, ferroptosis, autophagy, and inflammation [
101
].
In the context of ferroptosis, Nrf2 not only modulates intracellular iron, lipid, and redox
metabolism but also exerts influence on key ferroptosis inhibition pathways like GPX4
and FSP1 through intricate molecular interactions [
96
,
102
]. Reactive oxygen species (ROS)
generated during cellular stress trigger the activation of Nrf2 via the keap1-dependent
pathway [
103
]. And then, Nrf2 reduces intracellular iron by increasing the expression of
Fth and FPN, utilizing iron storage and iron effluence, respectively, and inhibits glia-driven
neuronal ferroptosis by positively regulating GPX4 and FSP1 pathways [
104
,
105
]. Netrin-1,
a binding protein associated with nerve regeneration, regulates ferroptosis after brain injury
by influencing Nrf2 through neurite inducible factor receptor UNC5B, providing a thera-
peutic direction for subsequent nerve recovery [
106
]. The peroxisome proliferator-activated
receptor PPAR
γ
pathway, which is associated with lipid metabolism, complements Nrf2
and significantly reduces ferroptosis and cognitive impairment in pathological models of
cerebral hemorrhage and cerebral ischemia [98,107,108].
In addition to its role in cell death and oxidative stress, recent research has highlighted
Nrf2’s involvement in neuroinflammation. Studies on cognitive function in offspring rats
subjected to maternal sleep deprivation have demonstrated that the ferroptosis inhibitor
liproxstatin-1 can reduce the release of inflammatory factors and the activation of microglia
via the Nrf2/HO-1 axis [
109
]. Similarly, in patients with neuroinflammation due to inter-
stitial cystitis and in models of RSL3-induced ferroptosis, Nrf2 has been observed to be
associated with pro-inflammatory cytokines and microglia [
110
,
111
]. In cases of traumatic
brain injury, Nrf2 promotes mitochondrial function recovery, enhances antioxidant capacity,
and inhibits neuroinflammation [
112
]. The mechanism by which Nrf2 regulates neuroin-
flammation is mainly dependent on its inhibition of downstream inflammatory pathways
by influencing the activation of NF-
κ
B (Figure 1). Nrf2 inhibits NF-
κ
B through various
means, including the induction of a shift in microglia from a pro-inflammatory M1 pheno-
type to an anti-inflammatory M2 phenotype via the Nrf2/STING/NF-
κ
B pathway [
113
,
114
].
The stimulator of interferon genes (STING), which serves as an immune sensor of endoge-
nous and exogenous DNA, may act as an intermediary in the NF-
κ
B induction by Nrf2
(Figure 1). While the relationship between Nrf2 and STING has been confirmed by the
STRING database, the cascading relationship between them remains to be elucidated [
115
].
The NRF2-STING axis plays a key role in regulating oxidative stress, inflammation, and
necrosis [
116
]. Activated STING can recruit TANK-binding kinase 1 (TBK1) to accelerate
the phosphorylation of NF-
κ
B [
117
]. In addition, heme oxygenase HO-1, the main regu-
latory enzyme of Nrf2, is believed to reduce NF-
κ
B activity [
118
]. Annexin A5 facilitates
phenotype transformation of microglia via the Nrf2 pathway to NF-
κ
B, counteracting the
inflammatory response, ferroptosis, and oxidative stress, thereby improving neurocognitive
dysfunction [
119
]. The effect of Nrf2 on neuroinflammation heavily relies on NF-
κ
B, but
the mechanisms by which Nrf2 regulates NF-
κ
B are varied. The association between these
two molecules remains incomplete, and the Nrf2/STING/TBK1/NF-
κ
B pathway in the
brain requires more detailed detection of protein expression and pathological experiments
for verification. In particular, the indirect relationship between Nrf2 and STING needs
further elaboration.
In summary, Nrf2, a key player in ferroptosis and oxidative stress, is significantly
involved in the connection between neuroinflammation and ferroptosis in the central
nervous system. However, our understanding of the molecular mechanisms underlying
neuroinflammation remains partial and incomplete. The downstream pathway activated
by Nrf2 within the complete neuroinflammatory signaling network should be viewed as
three-dimensional rather than linear, requiring further in-depth exploration and discussion.
4.1.3. NF-κB
Nuclear factor-
κ
B (NF-
κ
B) is a transcription factor found in all animal cell types that
plays a crucial role in immune and inflammatory responses [
120
]. As such, researchers
have focused on understanding the NF-
κ
B-related pathway, which presents a promising
Antioxidants 2024,13, 395 9 of 31
target for addressing a variety of pathological processes such as tumor progression, in-
jury, and inflammation [
121
–
123
]. The NF-
κ
B pathway has been implicated in regulating
neuroinflammation following central nervous system diseases, making it a particularly
important area of study [
124
]. Moreover, early research suggested, through kinase analysis,
that NF-
κ
B may play a critical role in ferroptosis [
125
]. Therefore, NF-
κ
B holds the potential
to emerge as a key focal point in the molecular mechanisms of both ferroptosis and neu-
roinflammation within the nervous system. A thorough understanding of the activation
process and mechanism of NF-
κ
B is essential for a more comprehensive prediction of the
resulting damage and identification of potential intervention targets in central nervous
system diseases.
Under normal physiological conditions, NF-
κ
B remains inactive, typically bound to
I-
κ
B-
α
in the cytoplasm. However, when there is a change in the cytoplasmic environment
or upon exposure to specific external stimuli, NF-
κ
B and I-
κ
B-
α
dissociate and translocate
into the nucleus, where they regulate the transcription of specific genes, thereby activating
NF-
κ
B [
103
] (Figure 1). In the context of neuroinflammation, common cellular triggers
that lead to NF-
κ
B activation include reactive oxygen species (ROS), damage-associated
molecular patterns (DAMPs), and lipopolysaccharides (LPSs) [103].
The generation of reactive oxygen species (ROS) is a key characteristic of cellular
ferroptosis, with the disruption of cellular iron homeostasis leading to a sudden increase
in intracellular ROS via the Fenton reaction [
12
]. In addition to instigating intracellular
lipid peroxidation and oxidative stress, ROS can also activate the NF-
κ
B pathway, thereby
triggering further inflammatory cascades [
126
]. A recent study on ferroptosis demonstrated
that reducing ROS-induced NF-
κ
B activation and inhibiting the resulting neuroinflamma-
tory response can be achieved through the use of the iron-chelating agent deferoxamine.
The study further proposed that these effects may be mediated, at least in part, by the
modulation of protein levels of p-NF-
κ
Bp65 [
126
]. This suggests that the regulation of
neuroinflammation from the standpoint of iron homeostasis is, to some extent, dependent
on NF-κB activity.
DAMPs serve as ubiquitous “warning signals” released from damaged or deceased
cells, including neurons and glial cells within the brain [
127
]. One prominent DAMP in
neuroinflammation is the high mobility group protein, HMGB1 [
128
]. In a study utilizing
ischemia-reperfusion injury as a model, it was observed that IRI led to an increase in
HMGB1 expression and upregulation of NF-
κ
B p65 in brain tissue. Interestingly, the
well-known ferroptosis inhibitor Fer-1 and its analogue Srs11-92 were able to reverse
this phenomenon [
129
]. Notably, annexin A5, an annexin protein, has been shown to
mitigate inflammation and ferroptosis following traumatic brain injury by targeting both
the HMGB1/NF-κB pathway and the Nrf2 pathway [119].
Lipopolysaccharides have the ability to directly induce neuroinflammation and are
frequently employed in constructing neuroinflammation models for numerous animal
and cell culture experiments. Research has illustrated that lipopolysaccharide-induced
neuroinflammation exerts its effects through the NF-
κ
B pathway in cells such as microglia
and neurons [130–132].
Within nerve cells, DAMPs and LPS function as ligands that bind to Toll-like receptor
4 (TLR4), initiating the activation of intracellular signaling pathways [
132
–
134
]. TLR4
triggers the activation of NF-
κ
B via a splice protein known as myeloid differentiation
primary response protein 88 (MyD88) [131,134] (Figure 1).
Upon entering the nucleus, NF-
κ
B activates the NLRP3 inflammasome and caspase-
1, consecutively. Subsequently, the activated caspase-1 converts the precursors of IL-1
β
and IL-18 into their active conformation [
126
]. The activation of the NF-
κ
B pathway in
innate immune cells within the brain ultimately elicits a shift towards a pro-inflammatory
phenotype, ultimately resulting in the release of pro-inflammatory cytokines including
TNF-
α
, IL-6, and IL-1
β
. These cytokines can exacerbate neuroinflammation [
135
,
136
].
Amongst these pro-inflammatory factors, IL-6 can contribute to ROS production [
103
],
Antioxidants 2024,13, 395 10 of 31
whereas TNF-
α
facilitates p65 binding factors to positively regulate NF-
κ
B via nuclear
signaling [
137
]. This amplifying effect may propagate inflammation throughout the brain.
The Fe
2+
/ROS/NF-
κ
B inflammatory pathway serves as a crucial link between iron
metabolism and cellular inflammation, offering a potential avenue for inhibiting neu-
roinflammation by regulating iron levels. Following brain injury, the administration
of the iron-chelating agent DFO has been shown to elevate the protein level of p-NF-
κ
Bp65. This intervention not only diminishes the activation and infiltration of neutrophils
and macrophages but also reverses the shift towards a pro-inflammatory phenotype in
microglia-like cells, ultimately ameliorating cognitive dysfunction in mice [
126
]. Further-
more, the classical inhibitory pathway of ferroptosis, the GPX4 pathway, is intricately
connected to the pro-inflammatory effects of NF-
κ
B. Studies indicate that GPX4 can impede
TNF-
α
-mediated NF-
κ
B transcriptional activity [
102
]. The capacity of Saikosaponin B2 to
suppress ferroptosis and neuroinflammation via the TLR4/NF-
κ
B pathway relies on the
presence of GPX4 [138].
NF-
κ
B is indirectly modulated by SIRT1 and Nrf2, while it also influences the ex-
pression of SIRT1 and Nrf2 through its transcriptional products (Figure 1). The NF-
κ
B
transcription-induced inflammasome NLRP3 hampers SIRT1 synthesis [
103
]. Research
indicates that the keap1-dependent pathway, which culminates in Nrf2 activation, is linked
to the transcriptional activity of NF-
κ
B p65 [
139
]. The interplay among the three intracellu-
lar regulatory molecules—SIRT1, Nrf2, and NF-
κ
B—dictates the fate of neurons and glial
cells. The cellular REDOX state may dictate the expression levels of these three proteins
in response to external stimuli, with this equilibrium ultimately determining whether the
nerve cell veers towards a pro-inflammatory and ferroptotic outcome.
4.1.4. PTGS2/Cox-2
PTGS2, also known as prostaglandin-endoperoxide synthase 2, is a gene that regulates
the synthesis of induced cyclooxygenase Cox-2. This physiological regulator catalyzes
arachidonic acid (AA) to produce prostaglandins (PGs) and acts as a peroxidase
[140,141]
.
Cox-2 is present in the human central nervous system under normal conditions and plays an
important role in brain functions such as memory [
142
]. However, under pathological con-
ditions, Cox-2 contributes to various neurodegenerative diseases and nerve injuries [
142
].
Elevated Cox-2 levels in cerebral stroke, traumatic brain injury, and neurodegeneration lead
to pathological changes including blood–brain barrier breakdown and cerebral edema [
143
–
146
]. Furthermore, due to its role in lipid peroxidation during the catalytic process AA,
Cox-2 serves as a lipid metabolic indicator of ferroptosis [
147
]. Additionally, Cox-2 is highly
expressed in inflammation and correlates with inflammatory factors such as IL-1
β
, IL-6,
and TNF-α[148].
Cox-2 primarily functions in acute inflammation, experiencing rapid upregulation
following neuroinflammation and returning to baseline levels within a few hours [
142
].
The transcription factor NF-
κ
B upregulates Cox-2 expression at the onset of inflammation
by binding to Cox-2 promoters [
149
]. In models of LPS-induced neuroinflammation, NF-
κ
B
upregulation leads to elevated levels of Cox-2 and iNOS, initiating a cascade of acute
inflammatory processes [
150
]. Given its crucial role in inflammation, Cox-2 inhibition
has emerged as a significant therapeutic target for various inflammatory conditions [
142
].
Inhibiting Cox-2 has been demonstrated to suppress microglial activation, thereby reducing
neuroinflammation, and downregulating Cox-2 also decreases NF-
κ
B expression [
151
].
For example, in mouse models post-splenectomy, administration of the Cox-2 inhibitor
meloxicam effectively mitigated neuroinflammation during the acute phase and alleviated
cognitive dysfunction in the chronic phase [152].
Research into the impact of Cox-2 on ferroptosis extends beyond lipid peroxidation.
Bioinformatics analysis has identified PTGS2 as a central gene in ferroptosis biology, closely
associated with key players such as ACSL4 and GPX4 [
153
]. The regulation of Cox-2 is
intertwined with ACSL4 expression, as evidenced by the concurrent decrease in Cox-2 con-
tent following ACSL4 gene knockdown [
154
]. Similarly, loss of GPX4 can result in increased
Antioxidants 2024,13, 395 11 of 31
PTGS2 expression [
155
]. Moreover, Cox-2 overexpression has been shown to diminish
glutathione (GSH) levels through its interaction with GPX4 [
156
]. Consequently, Cox-2
expression can be modulated through the conventional ferroptosis inhibition pathway. It
is evident that the expression of PTGS2 can be significantly elevated under the influence
of ferroptosis-specific inducers like RSL3 and erastin, thereby impacting arachidonic acid
metabolism and eicosanoid biosynthesis [
135
,
140
,
157
]. Conversely, Cox-2 inhibition can
also influence the extent of ferroptosis. For instance, in a diffuse brain injury model, meloxi-
cam treatment increased GSH levels and decreased malondialdehyde, an end product of
ferroptosis, over a 48 h period [
143
]. Additionally, atorvastatin has been demonstrated to
mitigate ferroptosis-induced myocardial injury through the PTGS2 pathway [158].
Particularly, research on the regulation of Cox-2 has revealed the existence of two
types of non-coding RNAs (ncRNAs). One type is microRNA, a single-stranded RNA
capable of binding to the 3’-untranslated region (UTR) of specific targeted mRNA [
140
].
The other type is long non-coding RNA (lncRNA), a long-stranded RNA that interferes
with mRNA splicing and influences downstream gene expression. Importantly, lncRNAs,
miRNAs, and downstream genes can form pathways that regulate proteins, known as com-
petitive endogenous RNAs (ceRNAs) [
159
]. Based on targetscan, a database for predicting
miRNA target genes, and bioinformatics analysis, ceRNAs have demonstrated exceptional
performance in regulating PTGS2/Cox-2. In various systems, evidence has shown that
miR-26a-5p and lncRNA Gm47283/miR-706 influence ferroptosis in bronchial epithelial
cells in COPD and myocardial infarction via PTGS2, respectively [
159
,
160
]. Similarly,
lncRNA-Cox2 serves as an inflammatory mediator, initiating a cascade of downstream
inflammatory reactions by inducing transcription of NF-
κ
B [
161
]. Numerous examples also
illustrate how microRNAs and lncRNAs regulate PTGS2 to impact neuroinflammation and
ferroptosis in brain disease models. For instance, miR-202-3p negatively regulates PTGS2
to attenuate neuroinflammation in IS [
162
]. In Alzheimer ’s disease, lncMALAT1 negatively
regulates the expression of Mir-125b-mediated PTGS2, while miR-103 promotes nerve re-
covery and growth by targeting PTGS2 [
163
,
164
]. Additionally, miR-137 from exosomes in
endothelial progenitor cells can counteract the neuroprotective effect of SH-SY5Y (derived
from neuroblasts) by inhibiting Cox-2 [
165
]. In rats, miR-194-5p targeting PTGS2 leads
to nerve damage in temporal lobe epilepsy [
166
]. Studies have also found examples of
miR-212-5p targeting PTGS2 to reverse ferroptosis in neurons in controlled cortical impact
mouse models [140].
Indeed, the discovery of ceRNAs as upstream targets of PTGS2 that regulate Cox-2
protein expression presents exciting potential for microRNAs to modulate neuroinflam-
mation and ferroptosis. As such, further research into the microRNA/PTGS2 pathway at
the gene level is crucial. This will not only enhance our understanding of the interplay
between neuroinflammation and ferroptosis in the central nervous system, but also pave
the way for the development of corresponding interventional strategies for treating various
clinical diseases.
4.1.5. iNOS/NO•
Inducible nitric oxide synthase (iNOS) is an enzyme primarily responsible for catalyz-
ing the synthesis of nitric oxide (NO). The metabolites of NO can generate nitroso salts,
leading to oxidative reduction metabolic disorders [
167
]. iNOS has been detected in nerve
damage caused by various factors and is closely associated with neuroinflammation and
neuropathic pain [
168
]. The expression of iNOS has also been found in diverse central
nervous system diseases, such as Alzheimer’s disease, Parkinson’s disease, ischemic brain
injury, and traumatic brain injury [
169
–
172
]. However, the specific mechanisms through
which iNOS influences the damage and long-term prognosis of these diseases are not
yet fully understood, as compared to other molecules. This article aims to explore its
relationship with ferroptosis and neuroinflammation in central nervous system diseases.
The neuroinflammation in the central nervous system caused by iNOS is closely linked
to microglia. During traumatic neuroinflammation, microglia-produced TNF-
α
activates
Antioxidants 2024,13, 395 12 of 31
the NF-
κ
B/iNOS pathway, leading to alterations in brain microcirculation function [
172
]
(Figure 1). This type of nerve injury is primarily characterized by damage to the blood–brain
barrier. In cerebral stroke, microglia rapidly produce iNOS upon cytokine stimulation [
150
].
Mechanistically, the regulation of iNOS mainly occurs at the transcriptional level and can
be influenced by downstream molecules in the neuroinflammatory signaling network,
consequently affecting upstream inflammatory factors. Following ischemic stroke, iNOS
production enhances the expression of CD14, thereby activating the TLR4/NF-
κ
B pathway
and inducing the generation of inflammatory factors [
171
]. In neuroinflammatory models
treated with LPS, microglia induce depression-like symptoms through the NLRP3/NF-
κ
B/iNOS signaling pathway [
173
]. In the treatment of epilepsy, miconazole alleviates
epilepsy symptoms by inhibiting both NF-
κ
B and iNOS [
174
]. Thus, the interaction between
NF-
κ
B and iNOS plays a pivotal role in the development of central nervous system diseases.
The activity of iNOS and the resulting NO production significantly impact the pheno-
type of microglia, potentially serving as a critical factor in triggering neuroinflammation.
LPS-treated microglia exhibit the M1 phenotype, accompanied by elevated levels of inflam-
matory factors and iNOS [
175
]. Studies indicate that the upregulation of iNOS/NO
•
and
the rise of reactive oxygen species (ROS) due to disrupted iron metabolism lead to height-
ened resistance to ferroptosis in M1-polarized microglia, promoting a global shift toward
the M1 phenotype [
176
,
177
]. This could explain the proinflammatory role of NO. Regarding
the mechanism through which iNOS inhibits ferroptosis in microglia and macrophages,
research has demonstrated that NO can independently regulate ferroptosis by suppressing
the production of 15-HpETE-PE [178,179].
However, focusing solely on the effect of iNOS on microglia is one-sided, as numerous
studies have demonstrated that iNOS and NO exert multiple effects on the ferroptosis of
various cell phenotypes. For instance, in individuals who smoke cigarettes, NO produced
by iNOS promotes ferroptosis in malignant mesothelioma (MM) cells through the pro-
duction of peroxynitrite [
180
]. Furthermore, iNOS activation leads to the upregulation of
ROS and RNS in triple-negative breast cancer cells, ultimately resulting in ferroptosis [
181
].
Interestingly, for the M1 and M2 phenotypes of macrophages, NO confers resistance to
ferroptosis [
182
]. Within the current research landscape, NO has exhibited a protective
effect against ferroptosis in certain immune cells, while demonstrating a sensitizing effect
in other cells. Unraveling the underlying reasons behind these contrasting effects warrants
further investigation.
Furthermore, contrary to the widely accepted notion of iNOS exerting detrimental
effects on central nervous system diseases, emerging evidence suggests that iNOS may
confer long-term protective effects on nerves [
183
]. This phenomenon could be attributed
to the bidirectional impact of NO on lipid peroxidation. In the short term, its generation of
peroxynitrite can mediate post-traumatic neuroinflammation and oxidative stress. How-
ever, owing to its ability to interact with other free radicals, NO also possesses unique
antioxidant properties [
183
], thereby safeguarding nerves in the long run. Consequently, a
comprehensive exploration of iNOS and NO warrants a closer examination of the temporal
dynamics of disease and the intricate interplay between NO and other free radicals.
4.2. Cell Phenotype and Specific Structure
4.2.1. Blood–Brain Barrier
The blood–brain barrier (BBB) plays a crucial role in facilitating communication be-
tween the brain and external substances. Any structural or functional abnormalities in the
BBB can result in brain injury and cognitive dysfunction. Notably, numerous neurodegen-
erative diseases are marked by the impairment of the blood–brain barrier, such as stroke,
traumatic brain injury (TBI), Alzheimer’s disease (AD), and Parkinson’s disease (PD) [
184
].
Therefore, it is imperative to gain a deeper understanding of the blood–brain barrier’s
involvement in the pathological processes of central nervous system diseases.
The blood–brain barrier is primarily composed of brain microvascular endothelial
cells, pericytes, basement membrane, astrocyte terminal feet, and intercellular tight junc-
Antioxidants 2024,13, 395 13 of 31
tion proteins, such as claudin-5 and ZO-1(Figure 2). Among these components, brain
microvascular endothelial cells (BMECs) and tight junction structures (TJs) play the most
crucial roles in determining the blood–brain barrier’s functionality [
185
,
186
]. Notably,
BMECs lack transcellular fenestrae, which restricts the transcellular exchange pathway
for substances. Additionally, the tight connection between BMECs minimizes intercellular
substance exchange. When the blood–brain barrier is compromised, it often results in the
infiltration of inflammatory mediators and toxic substances from the bloodstream into the
brain [
187
]. This can occur through the cell death of brain microvascular endothelial cells,
disruption of the tight junction structure, or a combination of both mechanisms, leading to
a cascade of brain injuries.
Antioxidants 2024, 13, x FOR PEER REVIEW 13 of 32
BBB can result in brain injury and cognitive dysfunction. Notably, numerous neurodegen-
erative diseases are marked by the impairment of the blood–brain barrier, such as stroke,
traumatic brain injury (TBI), Alzheimer’s disease (AD), and Parkinson’s disease (PD)
[184]. Therefore, it is imperative to gain a deeper understanding of the blood–brain bar-
rier’s involvement in the pathological processes of central nervous system diseases.
The blood–brain barrier is primarily composed of brain microvascular endothelial
cells, pericytes, basement membrane, astrocyte terminal feet, and intercellular tight junc-
tion proteins, such as claudin-5 and ZO-1(Figure 2). Among these components, brain mi-
crovascular endothelial cells (BMECs) and tight junction structures (TJs) play the most
crucial roles in determining the blood–brain barrier’s functionality [185,186]. Notably,
BMECs lack transcellular fenestrae, which restricts the transcellular exchange pathway for
substances. Additionally, the tight connection between BMECs minimizes intercellular
substance exchange. When the blood–brain barrier is compromised, it often results in the
infiltration of inflammatory mediators and toxic substances from the bloodstream into the
brain [187]. This can occur through the cell death of brain microvascular endothelial cells,
disruption of the tight junction structure, or a combination of both mechanisms, leading
to a cascade of brain injuries.
Figure 2. Structure of the blood–brain barrier and its intricate relationship with neuroinflammation
and ferroptosis. Serving as a crucial barrier between brain capillaries and the brain parenchyma, the
blood–brain barrier comprises brain endothelial cells, pericytes, and astrocytes, with a particular
emphasis on the tight junctions between brain endothelial cells. In instances of brain inflammation,
microglia are the primary instigators, releasing a plethora of inflammatory factors that disrupt the
internal environment of various cell types within the blood–brain barrier, leading to elevated levels
of iron and reactive oxygen species (ROS). Brain endothelial cells modulate the labile iron pool
through mechanisms such as TF/TFR, FtMt, and FPN, while astrocyte-secreted hepcidin can impact
the FPN activity of these endothelial cells. The accumulation of iron ultimately triggers ferroptosis
in the brain endothelial cells. Moreover, EMMPRIN on the cell surface activates the NF-κB pathway,
facilitating the secretion of MMP2/9, which in turn degrades tight junction proteins like occludin.
The resultant ferroptosis of endothelial cells and the breakdown of tight junction proteins are pri-
mary contributors to the compromise of the blood–brain barrier integrity. This breach allows in-
flammatory factors from the bloodstream and peripheral immune cells to infiltrate the brain paren-
Figure 2. Structure of the blood–brain barrier and its intricate relationship with neuroinflammation
and ferroptosis. Serving as a crucial barrier between brain capillaries and the brain parenchyma, the
blood–brain barrier comprises brain endothelial cells, pericytes, and astrocytes, with a particular
emphasis on the tight junctions between brain endothelial cells. In instances of brain inflammation,
microglia are the primary instigators, releasing a plethora of inflammatory factors that disrupt
the internal environment of various cell types within the blood–brain barrier, leading to elevated
levels of iron and reactive oxygen species (ROS). Brain endothelial cells modulate the labile iron
pool through mechanisms such as TF/TFR, FtMt, and FPN, while astrocyte-secreted hepcidin can
impact the FPN activity of these endothelial cells. The accumulation of iron ultimately triggers
ferroptosis in the brain endothelial cells. Moreover, EMMPRIN on the cell surface activates the
NF-
κ
B pathway, facilitating the secretion of MMP2/9, which in turn degrades tight junction proteins
like occludin. The resultant ferroptosis of endothelial cells and the breakdown of tight junction
proteins are primary contributors to the compromise of the blood–brain barrier integrity. This breach
allows inflammatory factors from the bloodstream and peripheral immune cells to infiltrate the brain
parenchyma, exacerbating neuroinflammation and eventual cell death within the brain parenchyma.
Abbreviations: Fpn, ferroportin; FtMt, ferritin mitochondrial; MMP2, matrix Metallopeptidase 2;
MMP9, matrix Metallopeptidase 9; NF-
κ
B, nuclear factor-kappaB; ROS, reactive oxygen species; TF,
transferrin; TFR, transferrin receptor. Solid arrows indicate promotion of expression or translocation.
Inhibition arrows denote suppression of expression. Dotted arrows represent chemical names.
Upward vertical arrows signify an increase in substance content. This figure was created with
BioRender.com.
Antioxidants 2024,13, 395 14 of 31
Understanding the molecular mechanisms underlying blood–brain barrier damage
and its consequences on the central nervous system is crucial due to the heavy reliance of
the central nervous system on the physiological state of the neurovascular unit (NVU) in the
brain [
188
]. Ferroptosis and neuroinflammation have emerged as significant mechanisms
implicated in the progression and outcomes of blood–brain barrier injury during disease
processes [
189
]. By comprehending these mechanisms, we can gain valuable insights
into the pathogenesis of central nervous system diseases and potentially develop targeted
therapeutic strategies.
Ferroptosis in brain microvascular endothelial cells plays a pivotal role in the compro-
mised integrity of the blood–brain barrier. This intricate process encompasses a multitude
of metabolic pathways and regulatory mechanisms, including iron metabolism, lipid
metabolism, glutathione metabolism, and the GPX4 pathway [
189
]. Disruption in any of
the components related to iron uptake, storage, or transport can elevate the labile iron pool
in BMECs, resulting in heightened permeability of the blood–brain barrier. Consequently,
BMECs transfer excess iron to neurons and glial cells in the brain via the transferrin and its
receptor (TF/TFR1) mechanism [
189
] (Figure 2). Notably, mitochondrial ferritin (FtMt) in
BMECs plays a crucial role in maintaining iron homeostasis by regulating iron storage [
190
]
(Figure 2). Research has indicated that ferroportin 1 (FPN1), an iron transporter in BMECs,
is regulated by hepcidin in astrocytes, underscoring the intricate intercellular regulation
within the blood–brain barrier [
191
]. Furthermore, the use of the iron chelating agent DFO
has been shown to reduce the labile iron pool in BMECs and protect the blood–brain bar-
rier through the HIF2
α
-Ve-Cadherin pathway [
192
]. Additionally, elevated levels of lipid
peroxidation products, such as MDA and 4HNE, have been observed in association with
blood–brain barrier disruption, concomitant with depleted GSH levels, emphasizing the
potential significance of REDOX regulation in preserving the integrity of the blood–brain
barrier [189].
In addition to BMECs, other components of the blood–brain barrier have also been
implicated in ferroptosis and its associated metabolic pathways. Notably, in the context
of Alzheimer’s disease treatment, A
β
1-40 has been found to facilitate iron overload and
lipid peroxidation in pericytes, thereby inducing blood–brain barrier impairment through
pericyte-mediated ferroptosis [
193
]. Moreover, lipid peroxidation can have an effect on the
blood–brain barrier by downregulating tight junction proteins, further compromising its
integrity [184].
In the study of different central nervous system diseases, researchers have discovered
that brain microvascular endothelial cells exhibit heightened sensitivity to ferroptosis
compared to other cell types [
194
]. In various models of brain injury resulting from cerebral
ischemia and hypoxia, Alzheimer’s disease, traumatic brain injury, and similar conditions,
ferroptosis triggered by BMECs has emerged as a crucial factor contributing to the loss of
blood–brain barrier integrity [
194
–
196
]. Considering the interplay between blood–brain
barrier cells and the impact of tight junction proteins affected by metabolites associated with
cell ferroptosis, it can be inferred that cell ferroptosis represents a significant underlying
cause of blood–brain barrier disruption.
Most central nervous system diseases are associated with neuroinflammatory cascades,
and the relationship between cerebral neuroinflammation and the blood–brain barrier
is bidirectional. Neuroinflammation contributes to an increase in blood–brain barrier
permeability due to various factors, while dysfunction of the blood–brain barrier leads
to an amplification of the neuroinflammatory response [
52
]. At the core of this positive
feedback loop is microglia, which can initiate inflammatory pathways following brain
damage from diverse causes, impact the structure of BMECs, and disrupt the tight junctions
of the blood–brain barrier through the release of inflammatory cytokines. Once the cell–cell
connections of the blood–brain barrier are compromised, the infiltration of peripheral
immune cells and exogenous neurotoxic substances further stimulate microglia [
52
,
197
].
This sequence of events encompasses several classic inflammatory manifestations, including
the release of TNF-
α
, IL-6, and IL-1
β
, as well as the transition of microglia from the M2
Antioxidants 2024,13, 395 15 of 31
to M1 phenotype [
198
,
199
]. In a particular study, researchers utilized lipopolysaccharide-
induced neuroinflammation to examine the microstructure of the blood–brain barrier.
Their findings revealed morphological changes in brain endothelial cells (BEC), such
as increased vesicles, plasma membrane shrinkage, mitochondrial abnormalities, and
extracellular expulsion. Additionally, notable oxidative stress characteristics were observed
in BECs [
200
]. Whether these morphological and functional alterations are linked to the
ferroptosis of BECs warrants further investigation.
In the progression of neuroinflammation, the destruction of the blood–brain bar-
rier leads to the invasion of peripheral circulating immune cells and other harmful sub-
stances, which is a significant mechanism for exacerbating brain injury (Figure 2). First,
the chemokines and cytokines released by peripheral immune cells can directly breach the
blood–brain barrier and activate the inflammatory response in the brain parenchyma [
200
].
Secondly, the infiltration of the peripheral immune cell barrier into the brain can lead to
damage of the original neurovascular unit (NVU) [
52
]. Finally, the proinflammatory pheno-
typic changes in microglia are also directly or indirectly associated with the infiltration of
peripheral cells [197].
Indeed, matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, play a
crucial role in the mechanism of blood–brain barrier damage [
201
]. These MMPs can be
induced by extracellular matrix metalloproteinase inducer (EMMPRIN). Elevated levels of
MMP-2/9 can lead to blood–brain barrier dysfunction by degrading tight junction proteins
like ZO-1 and occludin that maintain cellular integrity [
202
]. There are various regulatory
mechanisms for MMP-2/9. Evidence suggests that lipid peroxidation in endothelial cells
can upregulate MMP-2/9, leading to the breakdown of occludin [
184
]. Additionally,
activated microglia can stimulate MMP-2/9 by increasing EMMPRIN expression through
specific signaling pathways [
189
,
202
] (Figure 2). This information highlights how both
the process of ferroptosis in cells and neuroinflammatory manifestations can contribute
to blood–brain barrier damage through MMPs. EMMPRIN and MMP-2/9 may serve as
important links connecting neuroinflammation and cellular ferroptosis in the context of
the blood–brain barrier, making them potential targets for the treatment of central nervous
system diseases.
The molecular mechanisms underlying the onset and progression of blood–brain
barrier (BBB) injury are intricate, given its crucial role in separating and connecting the
central nervous system with the peripheral blood circulation. Following the emergence
of central nervous system diseases, neuroinflammation and the occurrence of ferroptosis
in brain microvascular endothelial cells (BMECs) and other cell types contribute to the
breakdown of the BBB’s essential structure. This heightened permeability of the BBB
not only fosters a cycle of neuroinflammatory responses but also gives rise to diverse
forms of neurovascular unit (NVU) cell death in the brain. In essence, ferroptosis and
neuroinflammation can act as both instigators and outcomes of BBB injury, respectively.
Pertinent inquiries arise: (a) What specific mechanisms underpin cell ferroptosis in causing
BBB damage? (b) Are the phenotypic changes in BMECs, driven by neuroinflammation
subsequent to central nervous system diseases, linked to its ferroptosis mechanism? (c) Is
the induced NVU cell death following BBB injury directly associated with alterations in
BMECs and tight junctions (TJs)?
4.2.2. Microglia
Microglia are a distinct type of glial cell found in the central nervous system, primarily
localized around neurons and the cerebrovasculature, and their population is relatively
small compared to other glial cells. Under normal, homeostatic conditions, resting microglia
serve essential physiological functions such as promoting nerve growth and constructing
synapses [
203
]. However, when the brain experiences injury or neurodegeneration, this del-
icate balance within the central nervous system is disrupted, leading to morphological and
functional changes in microglia as they become activated [48]. The activated microglia ex-
hibit diverse characteristics, and in order to facilitate the study of their function, researchers
Antioxidants 2024,13, 395 16 of 31
have traditionally classified their activation morphology into the pro-inflammatory M1
phenotype and the anti-inflammatory M2 phenotype [
204
]. This marked functional shift
may be attributed to differing metabolic profiles in the two phenotypes [
204
]. Throughout
the progression of central nervous system diseases, certain pathogenic molecules can in-
duce the transformation of microglia into the M1 phenotype. These pathogenic molecules
include pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharides,
cytokines like IFNγand GM-CSF, or DAMPs such as HMGB-1 or alpha-SYN [203].
Significantly, ferroptosis is intricately linked to phenotypic changes in microglia.
Firstly, iron metabolism in microglia plays a critical role in influencing its phenotypic
shifts. Research indicates that during the acute phase of Alzheimer’s disease or LPS-
induced neuroinflammation, the upregulation of divalent metal transporter 1 (DMT1) on the
microglial cell membrane results in iron overload and M1 polarization in microglia [
136
,
205
].
The activation of M1 phenotype microglia leads to the release of inflammatory factors such
as TNF-
α
, IL-1
β
, and IL-6, exacerbating neuroinflammation [
102
,
138
]. The classical iron
chelating agent DFO has been shown to help maintain iron homeostasis and partially
reverse M1 polarization of microglia [126].
Secondly, lipid peroxidation can induce the polarization of microglia towards the
M1 phenotype, thereby triggering microglia-mediated neuroinflammation [
206
]. Notably,
the signature molecule of ferroptosis, Acyl-CoA synthetase long-chain family member 4
(ACSL4), which regulates polyunsaturated fatty acids, has been implicated in enhancing
the release of inflammatory factors in microglia during stroke. The use of the ferroptosis
inhibitor liproxstatin-1 has demonstrated efficacy in reducing neuroinflammation resulting
from increased ACSL4 expression [
26
]. However, while ACSL4 in microglia does con-
tribute to the production of inflammatory cytokines, studies suggest that this mechanism
may be independent of ferroptosis. Data indicate that ACSL4 influences neuroinflam-
mation by affecting vestigial-like family member 4 (VGLL4), with no significant changes
in lipid peroxidation and cell-ferroptosis-related indicators observed following ACSL4
knockdown [206].
Finally, REDOX metabolism and related glutathione signaling pathways play a cru-
cial role in influencing phenotypic changes in microglia. Reduced levels of GPX4 in the
brain after injury result in the upregulation of reactive oxygen species (ROS), which in
turn enhances the pro-inflammatory response of microglia through the NF-
κ
B signaling
pathway [
126
,
135
]. Studies involving mice with GPX4 gene knockout have demonstrated
increased microglial activation and upregulation of neuroinflammatory markers [127].
Current research on the mechanism of ferroptosis on microglia phenotype has certain
limitations. This mechanism may be related to the varying levels of inducible nitric oxide
synthase (iNOS) in different cell phenotypes [
175
]. Regardless of whether it is the M1 or M2
phenotype, microglia can resist ferroptosis through the iNOS/nitric oxide (NO
•
) pathway.
However, the expression of iNOS in microglia of the M2 phenotype is relatively low, which
leads to the death of the M2 phenotype under conditions of iron overload [
176
]. Following
subarachnoid hemorrhage, the administration of L-NIL, an inhibitor of iNOS, can reverse
the number of M1 phenotypes in microglia and mitigate the extent of damage caused by
SAH [177].
In addition, the inflammatory effect of microglia is reflected in its role in mediating
the death of other nerve cells within the central nervous system. Microglia can disrupt the
blood–brain barrier by releasing pro-inflammatory factors that damage brain microvascular
endothelial cells and tight junction proteins [
52
]. Microglia activated prior to astrocytes
can influence astrocyte A1/A2 phenotypes through pro-inflammatory/anti-inflammatory
factors, thereby influencing astrocyte outcomes [
207
]. In mice with Parkinson’s disease,
microglia can induce ferroptosis in neuronal cells [107].
Microglia, as the core cells of central nervous system inflammation, play a crucial role
in mediating and perpetuating inflammation. They can be activated and migrate in response
to chemokines and cytokines released during inflammation, subsequently releasing pro-
inflammatory factors that contribute to the inflammatory cascade. Consequently, cell death
Antioxidants 2024,13, 395 17 of 31
and phenotypic changes within microglia themselves become significant factors in the
progression of inflammation. Several studies have demonstrated that the sensitivity of
microglia to ferroptosis, depending on their phenotypes, influences their polarization
during central nervous system inflammation, thereby exerting a comprehensive impact
on neuroinflammation. Furthermore, as cells undergoing ferroptosis release DAMPs that
promote neuroinflammation [
127
], the involvement of ferroptosis in other related cells
affected by microglia contributes to the pathological changes observed in central nervous
system diseases. However, the mechanisms through which microglia induce ferroptosis in
themselves and other nerve cells warrant further investigation.
4.2.3. Astrocytes
Astrocytes, the largest glial cell type, are ubiquitously present across mammalian
species. These cells play a pivotal role within the central nervous system, where their
primary functions span from maintaining ion homeostasis, metabolizing neurotransmitters,
and providing neurotrophic support to contributing to the integrity of the blood–brain
barrier [
53
,
208
–
210
]. Recent years have seen a surge in interest regarding the dynamic inter-
action between astrocytes and neurons. Beyond merely creating an optimal physiological
milieu for neuronal function, astrocytes emerge as autonomous information-processing
units that significantly influence the central nervous system’s overarching functional-
ity [211].
Astrocyte lesions play a critical role in a wide array of central nervous system dis-
eases, including traumatic brain injury, neurodegenerative disorders, and cerebrovascular
diseases. The pathophysiological changes observed in astrocytes during these conditions
typically include morphological atrophy, various modes of cell death, and the proliferation
of reactive astrocytes [
212
]. Among these, reactive astrocytosis has garnered significant
attention. Initially, much like microglia, reactive astrocytes were categorized into neurotoxic
(A1) and neuroprotective (A2) types, reflecting their dual roles in neural environments [
204
].
However, emerging perspectives suggest that astrocytes’ response to disease and trauma
is predominantly adaptive, thus primarily serving a neuroprotective function [
212
]. This
shift in understanding underscores the importance of focusing research on the functional
phenotypes of reactive glial cells rather than a binary classification, offering new insights
into astrocytes’ involvement in neuroinflammation.
Current research indicates that astrocytes undergo phenotypic transformations that
play a crucial role in modulating neuroinflammation, leading to the production of various
inflammatory cytokines and cytotoxic reactive oxygen species (ROS) [
49
]. Interestingly,
astrocytes can generate antioxidant enzymes under pathological conditions to mitigate ox-
idative stress [
49
]. During inflammation, astrocytes’ regulation of mitochondrial functions,
ROS, and antioxidant systems is pivotal in controlling their susceptibility to ferropto-
sis [
213
]. Building on this understanding and the intricate material exchanges between
astrocytes and neurons, we delve into the connection between astrocyte-driven neuroin-
flammation and ferroptosis, highlighting the complex interplay that influences disease
progression and potential therapeutic targets.
During the neuroinflammation of the telencephalon, astrocytes become activated,
identifiable by specific biomarkers such as GFAP, S100
β
, and CD81 [
49
,
214
]. The function-
ality of astrocytes is intricately linked to that of microglia, with various proinflammatory
and anti-inflammatory cytokines and chemokines serving as crucial mediators of their
interaction. Both cell types are capable of influencing the other’s phenotype through the
release of factors like TNF-
α
, which promotes inflammation, or TGF-
β
, which dampens it,
thereby either exacerbating or mitigating the inflammatory response [
49
,
204
]. Furthermore,
activated astrocytes can produce matrix metalloproteinases (MMPs), compromising the
blood–brain barrier and facilitating the influx of peripheral inflammatory cells into the
central nervous system, thereby intensifying the inflammatory milieu within the brain [
49
].
The release of pro-inflammatory and anti-inflammatory mediators during inflamma-
tion, coupled with oxidative stress-related enzymes, triggers the activation of intracellular
Antioxidants 2024,13, 395 18 of 31
receptors and signaling pathways. Notably, NADPH oxidase 4 (NOX4) in astrocytes
catalyzes the production of reactive oxygen species (ROS), further promoting neuroin-
flammation and mitochondrial damage [
215
]. This ROS-induced activity leads to lipid
peroxidation within cells, elevating levels of 4HNE and MDA and initiating ferroptosis in
astrocytes [
213
,
216
]. The activation of ROS also correlates with increased concentrations
of IL-1
β
, IL-6, TNF-
α
, and other inflammatory cytokines, suggesting a temporal over-
lap between the induction of astrocyte inflammation and ferroptosis. The upregulation
of glutathione peroxidase 4 in astrocytes acts as a defense mechanism against oxidative
stress-induced ferroptosis [49].
Moreover, the proinflammatory phenotype of astrocytes appears to be closely associ-
ated with the NF-
κ
B signaling pathway. The interplay between Nrf2 and NF-
κ
B pathways
is central to the molecular mechanisms underlying neurological diseases. Nrf2 can miti-
gate the expression of reactive astrocytes and reduce neuroinflammation and ferroptosis
by inhibiting NF-
κ
B [
217
,
218
]. The regulator of G protein signaling 5 (RGS5) can induce
neuroinflammation via the tumor necrosis factor receptor (TNFR) signaling pathway, con-
tributing to neurodegeneration in conditions like Parkinson’s disease, with TLR4 mediating
downstream factors of this pathway and regulating NF-
κ
B activation through nuclear
translocation [
131
,
219
]. Experiments treating angiotensin II (Ang II)-stimulated astrocytes
with the ferroptosis-specific inhibitor ferrostatin-1 have shown concurrent alterations in
astrocyte markers, inflammatory factors, and ferroptosis-related proteins [
58
]. Therefore,
there may be a common regulatory approach between astrocyte-induced neuroinflamma-
tion and cellular ferroptosis.
Furthermore, the process of inflammatory induction in astrocytes can trigger ferropto-
sis in neurons by altering the internal milieu of the central nervous system. Chemokines
derived from astrocyte activation, such as CXCL10/CXCR3, and the inflammatory cytokine
IL-6 can alter the expression of neuronal proteins, including Fpn, leading to an increase in
intracellular iron levels and ultimately resulting in neuronal ferroptosis [
29
,
220
]. However,
recent studies have indicated that the regulation of ferroptosis in neurons by astrocytes is
complex. Astrocytes may leverage the protective potential of Nrf2 to counter ferroptosis in
neurons by releasing exosomes [221].
4.2.4. Neutrophils and NETs
Neutrophils, originating from the bone marrow, are widely distributed in the blood-
stream and play a crucial role in acute inflammation, being the most prevalent cells during
its initial stages. Evidence suggests that the Neutrophil to Lymphocyte Ratio (NLR) is
associated with prognosis in certain central nervous system diseases [
222
–
224
]. How-
ever, the physiological blood–brain barrier presents a challenge for neutrophil entry into
the telencephalon. Consequently, the contribution of peripheral cells to central nervous
system diseases is often underestimated. Nevertheless, various pathological conditions
can compromise the blood–brain barrier, eventually allowing neutrophil infiltration. The
interplay between neutrophils and blood–brain barrier integrity is an unavoidable subject
in central nervous system diseases. Both systemic circulation and inflammatory factors in
the brain milieu can contribute to blood–brain barrier disruption [
225
]. Under pathologi-
cal conditions, chemokines and cytokines can drive neutrophil aggregation towards the
blood–brain barrier, further exacerbating its integrity [
226
]. Once the blood–brain barrier is
breached, neutrophils can infiltrate the brain, triggering neuroinflammation and damage to
the nervous system.
Recent advances have reshaped the understanding of neutrophils, highlighting their
diverse phenotypes and functions, contrary to the prior notion of their homogeneity [
227
].
Different neutrophil phenotypes play distinct roles in brain neuroinflammation [
228
].
Studies on neutrophil aging indicate that prolonged neutrophil survival amplifies their
pro-inflammatory impact on the brain [
229
]. Over the years, research on Neutrophil
Extracellular Traps (NETs) in neurological disorders has surged. NETs represent the
unique response of mature neutrophils to trauma and pathogens, forming a meshwork
Antioxidants 2024,13, 395 19 of 31
structure for self-destruction [
230
]. Co-culturing of NETs with nerve cells has demonstrated
their ability to provoke nerve cell inflammation. Additionally, ferroptosis in neutrophils
contributes to NET formation [
231
]. The inhibition of NET formation by ferroptosis inhibitor
ferrostatin-1 underscores the intimate link between ferroptosis and NET generation in
neutrophils [
231
]. Nonetheless, there is a lack of
in vivo
evidence of neutrophil ferroptosis
post-infiltration into brain tissue through the compromised blood–brain barrier, triggering
NET release and exacerbating neuroinflammation. Studies have shown that NETs modulate
ferroptosis in alveolar epithelium and breast cancer cell death through NF-
κ
B-related
pathways [
232
,
233
]. The intricate interplay among reactive oxygen species (ROS), NF-
κ
B,
and other inflammatory factors in inducing neuroinflammation and ferroptosis presents a
compelling avenue for exploring the processes and molecular mechanisms of NET-driven
ferroptosis and neuroinflammation in the brain.
Furthermore, both inflammatory cells and ferroptotic cells can release hypermigratory
histone box 1 (HMGB1), a protein that plays a crucial role in neutrophil recruitment [
234
].
Based on the aforementioned discoveries, we propose several hypotheses: In certain central
nervous system disorders, such as degenerative diseases and acute-phase conditions like
trauma, there may exist a detrimental cycle involving intracerebral nerve cells, peripheral
neutrophils, and intracerebral nerve cells. The release of DAMPs and inflammatory factors
during neuroinflammation of brain cells can lead to neutrophil recruitment and disruption
of the blood–brain barrier. Consequently, neutrophil infiltration into brain tissue occurs,
triggering their ferroptosis. Following ferroptosis, neutrophils release NETs, which can
further exacerbate the inflammatory response and neuronal death through interactions
with neurons.
4.2.5. T Cells
Lymphocytes are pivotal in orchestrating immune responses within the body. Based
on their morphology and function, they can be classified into B lymphocytes, T lympho-
cytes, and natural killer (NK) cells. In certain neurological conditions that incite chronic
neuroinflammation, both B and T cells have been observed to infiltrate the cerebrospinal
fluid, meninges, blood–brain barrier, and brain parenchyma [
51
,
235
–
237
]. Nevertheless,
extensive research indicates that T lymphocytes predominantly contribute to the pathogen-
esis of central nervous system diseases. B cells, on the other hand, play a crucial role in
maintaining the microenvironment and activating and sustaining the pro-inflammatory
function of T cells [235,236].
It is important to note that chemokines play a crucial role in the infiltration and
proliferation of T cells and B cells within the central nervous system. Chemokines can
be classified into four different subgroups: CXC, CC, CX3C, and XC [
238
]. Lymphocytes
express various chemokine receptors, which enable them to access different sites via the
chemokine ligand/receptor axis when chronic neuroinflammation occurs [239].
T lymphocytes are categorized into cytotoxic T cells (Tc cells), helper T cells (Th
cells), and regulatory T cells (Treg cells) based on their functions. These T lymphocytes
play a significant role in immune-related and chronic infectious neurological diseases by
releasing cytokines. Helper T cells, specifically Th1 and Th17 cells, are strongly associated
with neuroinflammation in the central nervous system. Research has demonstrated that
CNS astrocytes respond to cytokines released during Th1 and Th17 cell activation [
240
].
Th1 cells can secrete IFN-
γ
, which promotes the infiltration of T cells into the spinal cord.
Meanwhile, astrocytes partially inhibit T cell infiltration through the VCAM-1 receptor [
240
].
In the brain, the invasion of Th cells involves antigen-presenting cells (APCs) such as
boundary-associated macrophages (BAMs), classical dendritic cells (cDCs), and B cells [
237
].
Activation of Th1 and Th17 cells plays a critical role in promoting neuroinflammation by T
cells. Jinyuan et al. discovered that in multiple sclerosis, neurons undergoing ferroptosis
stimulate the activation of T cell receptor signaling pathways through the secretion of
various related molecules, leading to the activation of Th1 and Th17 cells and the release of
cytokines like IFN-γand IL-17 [241].
Antioxidants 2024,13, 395 20 of 31
CD8+ T cells are crucial cytotoxic T cells that have destructive effects on both brain
parenchyma and blood vessels. In chronic neuroinflammation, CD8+ T cells can infiltrate
and destroy blood vessels. In pathological models of cerebral malaria and Susac syndrome,
CD8+ T cells can damage cerebral vascular endothelial cells and decrease tight junction
protein expression via adhesion molecules such as VCAM-1 [
242
]. The breakdown of the
blood–brain barrier by CD8+ T cells ultimately leads to their infiltration into the brain
parenchyma [
51
]. Activated CD8+ T cells play a vital role in inducing ferroptosis in neurons,
which is confirmed by upregulation of related proteins such as TFR1 and ACSL4 in ECM
brain models [
243
]. Th cell activation by neuronal ferroptosis may locally exacerbate the
“vicious circle” of neuroinflammation [
51
]. Additionally, the infiltration of CD8+ T cells in
tau transgenic mice may activate microglia and astrocytes on the surface, leading to further
aggravation of neuroinflammation in the brain [
244
]. In contrast, Treg cells often display
neuroprotective effects, and their proliferation can be promoted by IL-2 secreted by helper
T cells [245]. Depleting Treg cells in cases of brain injury is not favorable for recovery.
Peripheral immune cells represent a promising area of research in the context of central
nervous system inflammation. While previous studies of CNS diseases have primarily
focused on the interaction between neurons and glial cells in situ, the significance of periph-
eral immune cells in the blood–brain barrier and brain parenchyma cannot be overlooked.
Particularly in certain chronic neuroinflammation disease models, there is evidence sug-
gesting that neuronal ferroptosis may both result from and contribute to the aggregation
and activation of T cells. The infiltration of immune cells exacerbates the disruption of
the nervous system’s physiological equilibrium and intensifies neuroinflammation. The
quantity and function of lymphocytes in numerous central nervous system disease models
warrant further investigation.
5. Conclusions
This review comprehensively summarizes the molecular mechanisms and cellular re-
sponses linked to ferroptosis and neuroinflammation in central neurological disorders. Our
literature search revealed a potential interplay between the metabolites of ferroptosis and
neuroinflammation, with each potentially acting as the initiator of the other process. While
the detailed pathogenesis varies, various central neurological disorders involve immune
cell activation in the brain, disruption of the blood–brain barrier, intracranial iron overload,
and peroxidation. These changes underscore the close correlation between ferroptosis and
neuroinflammation in the spatial and temporal distribution of each disease. Furthermore,
we focused on elucidating the specific mechanisms involving SIRT1, Nrf2, NF-
κ
B, Cox-2,
and iNOS/NO
•
molecules upstream and downstream of each other in central neurolog-
ical disorders, highlighting their connections with ferroptosis and neuroinflammation.
However, the relationships between these molecules are intricate, with many intermediate
processes still not fully understood. Moreover, the varying content of these regulatory
molecules in different nervous system cells significantly influences the susceptibility of
different cell phenotypes to ferroptosis and neuroinflammation. Future research on these
mechanisms could delve deeper into the following aspects: a. Intermediate processes
linking these associated molecules. b. Variances in the impact of different molecules over
time and across various cell phenotypes. c. The influence of peripheral immune cells on
the central nervous system environment.
6. Futures Perspectives
Given the intricate structure of the human brain and the diverse functions of nerve
cells, the treatment options for many central neurological disorders are currently limited.
Consequently, researchers are concentrating on exploring new molecular mechanisms
underlying these diseases. Ferroptosis, identified as a specific form of cell death, has
been implicated in various neurological disorders. By elucidating the interactive signaling
pathways and critical regulatory molecules connecting ferroptosis and neuroinflammation,
we have broadened the spectrum of potential therapeutic targets aimed at mitigating
Antioxidants 2024,13, 395 21 of 31
neurological damage in central nervous system disorders. For instance, resveratrol, which
modulates SIRT1, shows promise as a viable treatment for a range of neuroinflammatory
conditions [
93
]. Undoubtedly, further endeavors are imperative to translate anti-ferroptosis
or anti-inflammatory drugs into clinical practice. Apart from conducting phased animal
studies and clinical trials, enhancing the integration between the two pathways is equally
pivotal.
Author Contributions: Conceptualization, Y.X., Q.L. and C.L.; Writing—Original Draft Preparation,
Y.X. and C.L.; Review and Editing, B.J., J.L. and Q.L.; Funding Acquisition, C.L. All authors have read
and agreed to the published version of the manuscript.
Funding: This research was supported by the National Natural Science Foundation of China
(82271409, 81971163), Major project of National Natural Science Foundation of China (82293650,
82293651), Open project of Hebei Key Laboratory of Forensic Medicine (JYFY-23KF002), the outstand-
ing young backbone teacher of the “Blue Project” in Jiangsu Province (SR13450121), and a Project
Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions
(PAPD).
Conflicts of Interest: The authors declare no conflicts of interest.
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