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\begin{document}

\title{Role of ferroptosis in the occurrence and progression of acute ischemic
stroke}



\author[1]{Haoxiu Li}%
\author[1]{Meng Bi}%
\author[1]{Zhongqiang Cheng}%
\author[1]{Miao He}%
\author[2]{Weirong  Li}%
\affil[1]{Shanxi Medical University}%
\affil[2]{Shanxi Cardiovascular Hospital}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\selectlanguage{english}
\begin{abstract}
Ferroptosis is a new non-apoptotic form of regulatory cell death, which
is characterized by intracellular iron overload and excessive
accumulation of lipid peroxides and reactive oxygen species (ROS).
Ferroptosis is closely related to intracellular iron, amino acid, and
lipid metabolism disorders. Ferroptosis is increasingly recognized as an
important process mediating the pathogenesis and progression of acute
ischemic stroke, and it can be involved in influencing acute ischemic
stroke and acute ischemic stroke risk factors atherosclerosis, atrial
fibrillation, hypertension, diabetes mellitus, and obstructive sleep
apnea. Therefore, understanding the mechanisms of ferroptosis regulation
in different diseases may have significant implications for the
preventive treatment and improvement of prognosis in patients with acute
ischemic stroke and patients with risk factors for acute ischemic
stroke. This article reviews not only the specific important mechanisms
of ferroptosis in the development of acute ischemic stroke, but also the
relevant associations between risk factors for acute ischemic stroke and
ferroptosis, and describes the current limitations and future directions
of ferroptosis in the pathogenesis of acute ischemic stroke and its risk
factors.%
\end{abstract}%



\sloppy


\textbf{Role of ferroptosis in the occurrence and progression of acute
ischemic stroke}

\textbf{Haoxiu Li} \textsuperscript{\textbf{1}}
\textsuperscript{\textbf{+}}\textbf{,Meng
Bi\textsuperscript{1+},Zhongqiang Cheng\textsuperscript{1},Miao
He\textsuperscript{1},Weirong Li\textsuperscript{2*}}

\textsuperscript{1}Department of Neurology, Taiyuan Central Hospital,
Ninth Clinical College of Shanxi Medical University, Taiyuan, Shanxi,
China

\textsuperscript{2}Department of Neurology, Shanxi Cardiovascular
Disease~ Hospital, Taiyuan, Shanxi, China

\textbf{*Correspondence:} Weirong Li\emph{weironglee@163.com}

\textsuperscript{\textbf{+}} \textbf{Correspondence:}

\textbf{Haoxiu Li \textsuperscript{1+}and Meng Bi
\textsuperscript{1+}contributed equally to this work and share first
authorship.}

\textbf{Abstract:} Ferroptosis is a new non-apoptotic form of regulatory
cell death, which is characterized by intracellular iron overload and
excessive accumulation of lipid peroxides and reactive oxygen species
(ROS). Ferroptosis is closely related to intracellular iron, amino acid,
and lipid metabolism disorders. Ferroptosis is increasingly recognized
as an important process mediating the pathogenesis and progression of
acute ischemic stroke, and it can be involved in influencing acute
ischemic stroke and acute ischemic stroke risk factors atherosclerosis,
atrial fibrillation, hypertension, diabetes mellitus, and obstructive
sleep apnea. Therefore, understanding the mechanisms of ferroptosis
regulation in different diseases may have significant implications for
the preventive treatment and improvement of prognosis in patients with
acute ischemic stroke and patients with risk factors for acute ischemic
stroke. This article reviews not only the specific important mechanisms
of ferroptosis in the development of acute ischemic stroke, but also the
relevant associations between risk factors for acute ischemic stroke and
ferroptosis, and describes the current limitations and future directions
of ferroptosis in the pathogenesis of acute ischemic stroke and its risk
factors.

\textbf{Keywords:} Ferroptosis, Acute ischemic stroke,
Atherosclerosis, Atrial fibrillation,Hypertension.

\textbf{Introduction}

Acute ischemic stroke (AIS) is a disease caused by the insufficient
blood supply to the brain resulting in neuronal necrosis and brain
dysfunction, and is one of the leading causes of death and disability,
affecting millions of people worldwide\textsuperscript{1}. Ferroptosis
is a new form of non-apoptotic cell death first proposed by Dixon in
2012, which is characterized by intracellular iron overload and
excessive accumulation of lipid peroxides and reactive oxygen species
(ROS), and its occurrence is related to the three major metabolic
disorders of intracellular iron, amino acid, and
lipid\textsuperscript{2,3}. In recent years, more and more studies have
shown that ferroptosis is not only involved in the development of AIS
but also in the development of AIS risk factors such as atherosclerosis,
atrial fibrillation, hypertension, diabetes mellitus, obstructive sleep
apnea, and so on\textsuperscript{4-9}. The use of ferroptosis inhibitors
such as ferrostatin-1 and deferoxamine can not only prevent neuronal
cell death and reduce secondary brain injury after stroke to improve the
prognosis of patients but also slow the pathological progression of AIS
risk factors\textsuperscript{8,10-14}, which suggests that regulating
ferroptosis may become a new method for the prevention and treatment of
AIS. This article mainly reviews the research progress of the mechanism
of ferroptosis in AIS and its risk factor-related diseases, and by
understanding the specific mechanism of ferroptosis in stroke and its
risk factor-related diseases, it is expected to provide a reference for
the prevention and treatment of acute ischemic stroke by targeting
ferroptosis, to significantly improve the prognosis and survival of
patients.

\textbf{2. Ferroptosis and acute ischemic stroke}

\textbf{2.1 Disorder of iron metabolism leads to ferroptosis}

Iron is an important participant and regulator in the normal
physiological activity of the brain and is abundant in brain
tissue\textsuperscript{15,16}. Physiologically, the brain is protected
from whole-body iron fluctuations due to the protection provided by the
blood-brain barrier (BBB) \textsuperscript{17}. Under normal
circumstances, BBB endothelial cells through the transferrin receptor -
transferrin (TFR - TF) compounds mediated endocytosis of inactive iron
intake (Fe\textsuperscript{3+})\textsuperscript{18}, then through the
Six-transmembrane epithelial antigen of prostate 3 (STEAP3) convert
Fe\textsuperscript{3+} to free iron (Fe\textsuperscript{2+}).
Fe\textsuperscript{2+} is transported from endosomes by divalent metal
transporter 1 (DMT1) and exported to the extracellular space of the
brain by active transport or exocytosis mediated by ferroportin
(FPN)\textsuperscript{19,20}, and can also be stored in ferritin or the
labile iron pool (LIP)\textsuperscript{21}, which is involved in lipid
ROS production. Studies have shown that BBB capillary endothelial cells
can store and release iron in a regulated manner, thus acting as an iron
reservoir for the brain\textsuperscript{22}. Under acute ischemic
conditions, microglia are overactivated by ischemic stimuli, resulting
in disruption of the BBB\textsuperscript{23}, and free iron and ferritin
enter the brain parenchyma when the BBB is disrupted. Studies have shown
that the expressions of TFR1 and DMT1 can be significantly increased,
and the expression level of FPN can be decreased in the middle cerebral
artery ischemia model of MCAO rats\textsuperscript{24,25}, indicating
that the ability of intracellular iron uptake is enhanced and the
ability of iron efflux is weakened after cerebral ischemia, which will
eventually lead to intracellular iron overload. In addition, in the MCAO
rat model, the assembly of cytoplasmic NCOA4 protein in neurons is
significantly increased to recognize ferritin and transport it to
lysosome for degradation, resulting in a significant increase in the
concentration of free iron in neurons\textsuperscript{26}. Knockdown of
the \emph{NCOA4}gene can reduce the uptake of ferritin, avoid the
accumulation of free iron and eliminate the accumulation of reactive
oxygen species, thereby interfering with ferroptosis
\textsuperscript{27}. This suggests that NCOA4-mediated ferritin
autophagy is one of the additional key mechanisms mediating ferroptosis
in AIS. Therefore, any form of induced iron transport imbalance,
autophagic degradation of ferritin, and impairment of the blood-brain
barrier will lead to iron overload in the brain. Excessive intracellular
Fe\textsuperscript{2+} can not only generate ROS through the Fenton
reaction but also participate in the synthesis of lipoxygenase and then
catalyze lipid peroxidation\textsuperscript{28,29}. Lethal accumulation
of intracellular lipid peroxides as well as reactive oxygen species
promotes nuclear, protein, and membrane damage that ultimately mediates
cell death. Studies have shown that the increase of intracellular free
iron is positively correlated with the degree of neuronal damage after
ischemic stroke\textsuperscript{30}, which directly affects the recovery
of cerebral nerve function. In the early stages of ischemia-reperfusion,
iron overload increases the risk of bleeding transformation after early
tPA administration, accelerates ischemia-induced elevation of serum
matrix metalloproteinase-9, and enhances lipid peroxidation, thereby
increasing the likelihood of adverse outcomes\textsuperscript{31}. A
clinical trial reports that the use of the iron-chelating agent
deferoxamine to reduce systemic iron levels within 1-3 days of ischemic
stroke may be beneficial for short-term outcomes in patients with acute
ischemic stroke\textsuperscript{10}. It has also been proposed that the
use of ferroptosis inhibitors liproxstatin-1 and ferrostatin-1 can
reduce neurological dysfunction and cerebral infarct size in MCAO
mice\textsuperscript{32}. Therefore, rational application of ferroptosis
inhibitors such as deferoxamine to reduce the iron content in the brain
after AIS can reduce neuronal death and promote the recovery of
neurological function after ischemic stroke.

\textbf{2.2 Disorder of amino acid metabolism leads to ferroptosis}

System Xc- is a cystine/glutamic acid anti-transporter, which is
composed of light chain SLC7A11 and heavy chain SLC3A2, and is an
important intracellular antioxidant element. System Xc- exchanges
glutamate and cystine inside and outside the cell in a 1:1
ratio\textsuperscript{33}. Extracellular cystine is introduced into
cells via SLC7A11, the light chain of System Xc-. The cystine that
enters the cells is reduced to cysteine, and glutamic acid and glycine
are added to produce glutathione (GSH) under the catalyst of cysteine
ligase (GCL) and glutathione synthase (GSS), respectively. GSH is an
important antioxidant, which can enhance the anti-lipid peroxidation
activity of glutathione peroxidase 4 (GPX4). GPX4 can catalyze reduced
GSH into oxidized glutathione~(GSSG). Normally, reduced GSH accounts for
the majority, and GPX4 takes GSH as the substrate to react with lipid
peroxides to play an antioxidant role. Ultimately, it reduces the
occurrence of lipid peroxidation and ferroptosis and protects cells from
oxidative damage\textsuperscript{34}.

After acute ischemic stroke, excess extracellular glutamate inhibits the
activity of System Xc- by restricting cystine absorption, thereby
affecting GSH synthesis\textsuperscript{35}. In addition, acute ischemia
and hypoxia can increase the expression of BACH1, ATF3, and \emph{p53} ,
and these factors can reduce the uptake of cystine by neurons by
inhibiting the expression of System Xc- light chain SLC7A11, leading to
a decrease in GSH synthesis\textsuperscript{36-38}. Other studies have
suggested that GPX4 protein expression and activity decreased after
acute ischemic stroke \textsuperscript{39}. The abnormal function of
these specific factors can lead to the accumulation of lipid peroxides
in cells and eventually ferroptosis. The above results suggest that
ferroptosis of cells caused by amino acid metabolism disorder after AIS
is manifested in the following three aspects: (1) inhibition of System
Xc-; (2) decreased glutathione synthesis; (3) The expression and
activity of GPX4 were decreased. This suggests that ferroptosis can be
inhibited by intervening in the above process, and related studies have
used some drugs to intervene in the above process to inhibit the
occurrence of ferroptosis. Some studies have shown that galangin and
Naotaifang extracts can inhibit ferroptosis and reduce neuronal cell
death by enhancing the expression of SLC7A11 and
GPX4\textsuperscript{24,40}. Edaravone is an antioxidant protective
agent that effectively inhibits ferroptosis caused by decreased GSH
content caused by cystine deficiency\textsuperscript{41}. Furthermore,
in the rat ischemic stroke model, it was found that edaravone treatment
reduced Fe\textsuperscript{2+}, MDA, and LPO in the brain tissue,
increased GSH content, and up-regulated GPX4 expression, suggesting that
edaravone could inhibit ferroptosis and attenuate cerebral
ischemia-reperfusion injury\textsuperscript{25}. Edaravone is currently
used in the treatment of acute ischemic stroke. Research shows that
post-tMCAO selenium treatment significantly reduces cerebral infarct
volume, oxidative stress, and ferroptosis and enhances post-tMCAO motor
performance in the acute phase after
stroke\textsuperscript{42}.~Carvacrol can inhibit ferroptosis by
enhancing GPX4 expression, thereby rescuing hippocampal neuronal injury
induced by reperfusion \textsuperscript{43}. Icariin has been shown to
have a neuroprotective effect against acute ischemic
stroke\textsuperscript{44}. In a study of the action and mechanism of
icariin as a synovitis therapeutic agent, it was found that icariin
enhances cell survival in lipopolysaccharide-induced synoviocytes by
suppressing ferroptosis via the Xc-/GPX4 axis\textsuperscript{45}.
However, there is still a lack of relevant studies on the effect of
icariin on anti-ferroptosis to improve the prognosis of AIS. Therefore,
regulating amino acid metabolism and GPX4 expression can reduce neuronal
ferroptosis and promote brain injury recovery after AIS. In the future,
more sensitive drugs can be developed to inhibit ferroptosis according
to the specific mechanism of amino acid metabolism disorders, to improve
the treatment and prognosis of AIS.

\textbf{2.3 Dysregulation of lipid metabolism leads to ferroptosis}

Neuronal cells are prone to ferroptosis caused by iron-dependent lipid
ROS accumulation, mainly because the brain is rich in polyunsaturated
fatty acids (PUFAs), which are susceptible to lipoxygenases and reactive
oxygen species (ROS) to generate lipid peroxides\textsuperscript{46}.
PUFAs, especially arachidonic acid (AA) and adrenic acid (ADA) are
highly susceptible to oxidation and subsequently lead to the
accumulation of lipid peroxides (LOOH) and ROS \textsuperscript{47}.
Acyl-CoA synthetase long-chain family member 4 (ACSL4) and
lyso-phosphatidylcholine acyltransferase-3 (LPCAT3), as promoters of the
esterification of AA and ADA into PE, play an important role in the
formation of AA/ADA-PE\textsuperscript{48,49}. AA/AdA-PE is converted to
the harmful PE-AA-OOH or PE-ADA-OOH by lipoxygenase (LOXs) through
enzymatic or non-enzymatic lipid peroxidation, resulting in the
formation of large amounts of lipid peroxides, which leads to the
destruction of membrane integrity and ferroptosis
\textsuperscript{50,51}.

ACSL4 is widely expressed in brain tissue, and as a potential target of
miR-347 after cerebral ischemia, it is upregulated with over-expression
of miR-347 after cerebral ischemia in mice, inducing neuronal
death\textsuperscript{52}. Some studies have proposed that upregulation
of thrombin after acute cerebral ischemia reperfusion can promote
arachidonic acid mobilization by not affecting intracellular Fe2+ level,
and then catalyzed esterification by ACSL4 stimulates ferroptosis signal
transduction, leading to ferroptosis of neuronal cells. The results of
this study strongly suggest that antithrombin therapy may be beneficial
to post-stroke reperfusion by inhibiting ferroptosis\textsuperscript{4}.
It is worth further study. ACSL4 also promotes the production of
pro-inflammatory cytokines tumor necrosis factor-\selectlanguage{greek}α \selectlanguage{english}(TNF-\selectlanguage{greek}α\selectlanguage{english}),
interleukin-6(IL-6), and interleukin-1\selectlanguage{greek}β \selectlanguage{english}(IL-1\selectlanguage{greek}β\selectlanguage{english}) by microglia, which
further exacerbates brain injury by promoting the inflammatory response
after AIS\textsuperscript{53}. It was found that ACSL4 expression was
increased in a mouse model of ischemic stroke, and inhibition of ACSL4
with rosiglitazone significantly improved neurological function and
reduced infarct volume 72 h after stroke\textsuperscript{39}. These
studies suggest that ACSL4 may be a novel regulator of neuronal death
and neuroinflammation, and intervention of ACSL4 expression may be a
potential therapeutic target for ischemic stroke. However, there are
still few related studies in this field, so more studies should be
conducted in the future to reveal the specific mechanism of action of
ACSL4 in the occurrence of ferroptosis in patients with ischemic stroke.

LOXs are key enzymes in the induction of
ferroptosis\textsuperscript{54}. There are several subtypes of LOXs, of
which 12/15-LOX is a particular subtype. The study found that after
focal ischemia, 12/15-LOX was increased in neurons and endothelial
cells. Overexpression of 12/15-LOX leads to neuronal death in the brain
and disruption of the blood-cerebrospinal fluid barrier, and the use of
12/15-LOX inhibitors can improve neurological function and reduce
cerebral edema\textsuperscript{55}. And research has found that
12/15-LOX is up-regulated following global cerebral ischemia, and
contributes to neuronal injury. Either gene knockout or treatment with
the 12/15-LOX inhibitor LOXBlock-1 reduce injury and improve
neurological outcome\textsuperscript{56}. These findings suggest that
increased expression of 12/15-LOX is involved in neuronal cell death
after cerebral ischemia, and its inhibitor may be a novel therapeutic
approach for alleviating cerebral ischemia injury. However, whether
12/15-LOX is involved in post-AIS neuronal cell death mainly by
mediating ferroptosis remains unclear and deserves further study.

\textbf{(Figure 1)}

\textbf{3. Risk factors associated with ferroptosis and acute ischemic
stroke}

\textbf{3.1 Ferroptosis and atherosclerosis}

Atherosclerosis (AS) is the most common cause of acute ischemic stroke,
which is related to the TOAST classification of large artery
atherosclerosis. Therefore, a more precise understanding of the
pathological mechanism of the occurrence and progression of AS may
benefit patients in preventing AIS. Studies have found that ferroptosis
is closely related to the occurrence of AS and participates in various
pathophysiological processes of AS\textsuperscript{57}.

\textbf{3.1.1 Ferroptosis is involved in endothelial dysfunction in AS}

An important mechanism by which ferroptosis occurs is iron overload.
Studies have found that chronic iron overload can exacerbate the
atherosclerotic process, which is associated with oxidative stress and
vascular endothelial dysfunction \textsuperscript{58,59}. A clinical
trial has reported that iron levels increase in carotid atherosclerotic
lesions compared to normal healthy human endothelium and are further
elevated in advanced AS, inducing oxidative stress and inflammatory
responses\textsuperscript{60}. Induced oxidative stress is mainly
manifested by excessively stored iron leading to peroxidative damage in
the inner wall of the artery by increasing the production of oxygen free
radicals, which further aggravates AS. Inflammatory response induction
mainly shows that with the progression of the disease, long-term iron
overload leads to the increase and dominance of M1 macrophages, which
can secrete pro-inflammatory factor TNF-\selectlanguage{greek}α, \selectlanguage{english}etc\textsuperscript{61}.
Blood vessels infiltrated by long-term inflammatory factors are prone to
the aggregation and oxidation of LDL, promoting the formation of foam
cells and the deposition of atherosclerotic plaques. In turn, it
promotes the development of AS and ferroptosis of macrophages in
plaques\textsuperscript{62}. Administration of ferroptosis inhibitor
ferrostatin-1 significantly ameliorated ROS-induced lipid peroxidation
and endothelial dysfunction, thereby attenuating atherosclerotic
lesions\textsuperscript{11}. A recent study demonstrated for the first
time that ionizing radiation can induce ferroptosis in endothelial cells
through NCOA4-mediated ferritin autophagy to promote plaque progression
in AS. At the same time, this study also proposed that the knockdown of
NCOA4 has a therapeutic effect in alleviating ionizing radiation-induced
ferroptosis in endothelial cells\textsuperscript{63}. The above studies
suggest that ferroptosis is involved in endothelial dysfunction and
plays an important role in the occurrence and development of AS.

\textbf{3.1.2 Ferroptosis is involved in AS foam cell formation and
death and promotes plaque formation}

HIF-1\selectlanguage{greek}α, \selectlanguage{english}an upregulated DEG between atherosclerosis and normal,
co-regulates autophagy and ferroptosis. HIF-1\selectlanguage{greek}α \selectlanguage{english}inhibitor PX-478
attenuates foam cell formation and lessens atherosclerosis by enhancing
autophagy and depressing ferroptosis in macrophages\textsuperscript{64}.
Nuclear factor NF-E2-related factor (Nrf2) has been considered as a
major regulator of antioxidant in previous studies, which can mediate
the transcriptional regulation of multiple target genes and play a key
role in regulating ferroptosis. It was found that by inducing a
macrophage autophagy defect model, the Nrf2-mediated antioxidant defense
was turned off, while the negative effects of Nrf2 manipulation were
initiated, leading to iron deposition and lipid peroxidation, and
finally ferroptosis of foam cells\textsuperscript{65}. It has also been
shown that a high level of uric acid-induced iron death in macrophages
is involved in the formation of atherosclerotic plaques. More
importantly, inhibition of ferroptosis by activation of Nrf2 may
attenuate atherosclerosis induced by high levels of uric
acid\textsuperscript{5}. In conclusion, ferroptosis is not only involved
in inducing the formation and death of foam cells in AS but also in
promoting the formation of AS plaques. At the same time, the regulation
of the Nrf2 pathway may be an important mechanism of ferroptosis
resistance in AS.

\textbf{3.1.3 Ferroptosis is involved in inducing plaque progression in
AS}

Plaque rupture, intra-plaque bleeding, and thrombosis are also important
causes of AS progression. In the process of plaque formation in the late
stage of human carotid artery atherosclerosis, oxygen consumption in the
blood vessel wall increases and plaque lesions undergo hypoxia, which
stimulates angiogenesis and the resulting blood vessels are highly
permeable and brittle\textsuperscript{66}. Moreover, advanced plaques
contain a large number of macrophages with pro-inflammatory phenotypes
that secrete stroma-degrading enzymes, leading to plaque instability,
plaque rupture, intra-plaque bleeding, and thrombotic
events\textsuperscript{67}.

GPX4 is an important antioxidant and plays an anti-ferroptosis role in
the body. The severity of atherosclerosis was negatively correlated with
GPX4 expression\textsuperscript{68}. Overexpression of GPX4 inhibits the
development of atherosclerosis by decreasing lipid peroxidation and
inhibiting the sensitivity of vascular cells to oxidized
lipids\textsuperscript{69}. By up-regulating GPX4 expression and
enhancing GPX4 catalytic activity, vascular smooth muscle cell
proliferation can be inhibited and arterial protection can be
enhanced\textsuperscript{70}. A single dose of selenium delivered to the
brain promotes the expression of the antioxidant GPX4, protects neurons,
and inhibits plaque growth in AS\textsuperscript{71}. It was found that
Qing-Xin-Jie-Yu Granule partially inhibited ferroptosis in vulnerable AS
plaques through GPX4/ Xc- signaling pathway and weakened AS
progression\textsuperscript{72}. Thus, upregulation of GPX4 expression
can slow plaque progression in AS by inhibiting ferroptosis.

Long non-coding RNAs (lncRNAs) have been associated with atherosclerosis
(AS), and lncRNA PVT1 was found to be significantly upregulated in serum
of patients with AS. In vitro experiments using human vascular
endothelial cells (HUVECs) showed that knockdown of PVT1 and miR-106b-5p
overexpression inhibited increases in iron content, MDA levels, lipid
ROS, ACSL4, and PTGS2, as well as decreases in GSH and GPX4 in
oxygen-LDL-induced HUVECs. The study also found that PVT1 knockdown
decreased lipid deposition, atherosclerotic plaque number and size in
ApoE mice. These results suggest that PVT1 plays a key role in the
progression of AS by regulating the miR-106b-5p/ACSL4 axis in HUVECs,
and therefore may be a potential therapeutic target for
AS\textsuperscript{73}.

\textbf{3.1.4 Possible ferroptosis biomarkers for AS}

Prostaglandin peroxidase synthase 2 (PTGS2) gene encodes cyclic
oxygenase-2 (COX-2)\textsuperscript{74}. PTGS2 has been proposed as a
potential ferroptosis-related biomarker for ischemic
stroke\textsuperscript{75}. The pathological analysis of human coronary
arteries showed that the late ferroptosis-related proteins PTGS2 and
ACSL4 were up-regulated, while GPX4 was down-regulated. The severity of
atherosclerosis was positively correlated with the expression of PTGS2
and ACSL4, and negatively correlated with the expression of GPX4. This
study further confirmed that cellular ferroptosis can regulate the
development and progression of atherosclerosis. The study also suggests
that \emph{PTGS2} may be a central gene in
atherosclerosis\textsuperscript{68}. Then, by constructing a
protein-protein interaction (PPI) network and histological verification
of related genes, five AS-related ferroptosis hub genes (\emph{TP53}
,\emph{MAPK1} , \emph{STAT3} , \emph{HMOX1} , and \emph{PTGS2} ) were
finally identified. This study further demonstrated that \emph{PTGS2}
may be a key hub gene for AS and its expressed protein may serve as a
biomarker of atherosclerosis severity\textsuperscript{76}. These
findings may provide new ideas and potential targets for the prevention
and treatment of atherosclerosis. Atherosclerosis eventually leads to
clot deposits and narrowing of blood vessels, which reduces blood flow
to the brain and restricts oxygen supply, eventually leading to
hypoxia-ischemia and AIS. Therefore, it is necessary to understand the
specific mechanism of ferroptosis in AS, so AS to provide thinking for
the treatment of AS and prevention of AIS by targeting ferroptosis.
However, research on ferroptosis and AS is still in its infancy. More
studies will reveal the specific molecular mechanism of ferroptosis and
thus provide more evidence for ferroptosis prevention and treatment of
AS. \textbf{(Figure 2)}

\textbf{3.2 Ferroptosis and atrial fibrillation}

Atrial fibrillation (AF) is an important risk factor for AIS, resulting
in a five-fold increased risk of stroke and two-fold increased
mortality\textsuperscript{77}. Atrial fibrillation (AF) is also one of
the most common preventable causes of AIS and is often associated with
cardiogenic stroke. Compared with other ischemic stroke subtypes,
cardiogenic stroke is associated with more severe severity, poorer
prognosis, and a relatively higher recurrence rate\textsuperscript{78}.
Therefore, understanding the pathogenesis of atrial fibrillation and
selecting appropriate drugs based on the pathological mechanism may
greatly help the treatment and prognosis of patients with cardiogenic
stroke.

\textbf{3.2.1 Ferroptosis is involved in the occurrence of AF}

Iron overload and oxidative stress are essential pathological processes
in ferroptosis. Studies have confirmed that iron overload and oxidative
stress affect cardiac pathophysiology and can lead to
AF\textsuperscript{79,80}. Nomani et al. found that AF was more common
in beta-thalassemia patients than in the normal population, for whom
iron overload of the heart and iron-dependent oxidative stress is one of
the most important causes of atrial fibrillation\textsuperscript{81}.

Iron overload is related to AF occurrence. It was found that AF was
induced by chronic iron overload\textsuperscript{79}. FPN mediates iron
efflux, an important protein that regulates iron and calcium homeostasis
in cells. After knocking out FPN, rats' intracellular iron concentration
and oxidative stress were further increased, and AF was more likely to
be induced\textsuperscript{12}.

Oxidative stress is associated with AF occurrence. In myocardial tissue,
elevated ROS levels are associated with AF. Elevated ROS levels lead to
protein, lipid, and DNA damage, and are also involved in cardiac
structural and electrical remodeling, increasing susceptibility to
AF\textsuperscript{82,83}. Connexin distribution and protein level
changes were associated with enhanced AF
susceptibility\textsuperscript{84}. Studies have found that ROS may
induce AF by decreasing the expression of connexin 40 and connexin
43\textsuperscript{85}.

Given the above basis, it has been confirmed that ferroptosis occurs in
AF. This study pointed out that cardiac fibroblasts promote the
ferroptosis of cardiomyocytes by secreting exosomes, and reduce the loss
of cardiomyocytes and oxidative stress damage by interfering with
exosome miRNA, which can prevent the continuous development of
AF\textsuperscript{6}.

\textbf{3.2.2 Different AF risk factors affect AF susceptibility by
regulating ferroptosis}

Alcohol consumption is one of the common risk factors for AF. A study on
the effect of ferroptosis on the susceptibility to AF at different
drinking frequencies indicated that frequent excessive drinking would
activate ferroptosis and increase the induction rate of AF. Inhibition
of ferroptosis could balance the iron overload disorder and reduce the
production of reactive oxygen species (ROS), ultimately reducing the
susceptibility to AF\textsuperscript{86}. Another study to explore the
pharmacological effects of icariin on ethanol-induced atrial remodeling
found that excessive ethanol use resulted in severe atrial damage, as
indicated by increased susceptibility to AF, altered atrial conduction
patterns, enhanced atrial enlargement and fibrosis markers, and
up-regulation of ferroptosis related proteins (PTGS2, ACSL4, P53). The
expression of anti-ferroptosis-related molecules (GPX4, FTH1) was
down-regulated, and these deleterious effects were reversed by treatment
with ferrostatin-1 or icariin\textsuperscript{87}.

Obesity is an important risk factor for AF and intestinal microbiota
imbalance plays an important role in the pathogenesis of obesity-related
AF, which can increase LPS and cause atrial pathological remodeling by
activating ferroptosis and inflammasome signaling pathways. Inhibition
of ferroptosis or inflammasome signaling significantly ameliorated
atrial fibrosis and reduced susceptibility to obesity-related intestinal
dysbiosis-induced AF\textsuperscript{88}.

Sepsis is a risk factor for new-onset AF, and ferroptosis is involved in
the development of sepsis-induced organ damage. In a recent study,
researchers generated an LPS-induced endotoxemia model to understand the
mechanism of the link between sepsis-induced ferroptosis and atrial
fibrillation. Selective knockdown of Fpn using gene transfection
technology was found to increase the intracellular iron concentration
and oxidative stress and increase the susceptibility of LPS-induced
endotoxemia rats to AF\textsuperscript{12}. \textbf{(Figure 3)}

The above studies have shown that ferroptosis plays an important role in
the pathogenesis of atrial fibrillation susceptibility, and intervention
of ferroptosis can reduce the susceptibility and progression of AF.
However, there is still a lack of relevant research on the specific
mechanism of AF and ferroptosis. Clinically, whether the use of
ferroptosis inhibitors can reduce the incidence of cardiac stroke and
improve the prognosis of some patients who are susceptible to AF or who
have already suffered from AF requires further exploration and research
by more scholars.

\textbf{3.3 Ferroptosis and hypertension}

Hypertension is one of the risk factors for cardiovascular and
cerebrovascular diseases such as atherosclerosis and ischemic stroke.
Its pathophysiological mechanism is mainly related to increased vascular
resistance, manifested by endothelial dysfunction, increased
vasoconstriction, and arterial remodeling. In recent years, more and
more studies have found that ferroptosis is closely related to the
occurrence and development of hypertension\textsuperscript{7,89}.
Therefore, understanding the specific relationship between ferroptosis
and hypertension will be of great benefit to the treatment of
hypertension and the prevention of cerebrovascular disease complications
caused by hypertension.

\textbf{3.3.1 Ferroptosis is involved in the pathophysiology of
hypertension}

Existing studies have found that ferroptosis is involved in endothelial
cell dysfunction, which can lead to changes in vasomotor function and
cause hypertension\textsuperscript{11}. Vascular smooth muscle cells
(VSMCs), as one of the main cellular components of the vascular wall,
can maintain the tension of the vascular wall through a slow and mild
contraction. The phenotypic transformation of VSMCs is closely related
to the pathophysiological process of hypertension. Recent studies have
found that ferroptosis can induce the transition of VSMCs from
contractile phenotype to synthetic phenotype\textsuperscript{90}. This
suggests that ferroptosis is related to the pathogenesis of
hypertension.

Many studies have shown that ROS plays an important role in vascular
remodeling and endothelial dysfunction associated with hypertension.
Increased ROS can promote endothelial dysfunction, and accelerate VSMCs
proliferation and vascular remodeling, leading to vascular injury,
increased peripheral resistance, and elevated blood
pressure\textsuperscript{91,92}. An important feature of ferroptosis is
an increase in intracellular ROS levels. A recent in vitro study found
that VSMC undergoes ferroptosis under high hydrostatic pressure,
accompanied by iron accumulation, increased ROS production, and lipid
peroxidation\textsuperscript{7}.In addition, it has been proposed that
lenvatinib can induce ferroptosis in endothelial cells, which
subsequently leads to vascular dysfunction and
hypertension\textsuperscript{13}. The above studies have proved that
ferroptosis is involved in the pathophysiology of hypertension.

\textbf{3.3.2 Possible ferroptosis biomarkers in Hypertension}

It has been mentioned above that PTGS2 may be a potential biomarker of
iron death in AIS and AS, and PTGS2 encodes COX-2. COX-2 has been
implicated in increased vascular hardness and extracellular matrix
deposition, increased vasoconstriction response, endothelial
dysfunction, and vascular inflammation. Reduction of COX-2 can reduce
vasoconstriction response and endothelial dysfunction, and reduce the
increase in vascular hardness in hypertensive
animals\textsuperscript{93}. It was found that high hydrostatic pressure
induced iron death in VSMC, accompanied by up-regulation of
COX-2\textsuperscript{7}. Reducing COX-2 expression can improve
endothelial function and slow the progression of
hypertension\textsuperscript{94}. In conclusion, it is suggested that
COX-2 may be a biomarker of ferroptosis in hypertension, which can be
proved by more studies in the future.

\textbf{3.3.3 Antiferroptosis may be a new target for hypertension
treatment in the future}

Nrf2 can activate the transcription of target antioxidant genes and play
a key role in the oxidation reduction reaction regulation of
hypertension\textsuperscript{95}. Studies have found that inhibiting
Nrf2 can promote oxidative stress and inflammation, and further
aggravate hypertension in mice\textsuperscript{96}. On the contrary, it
promoted Nrf2 signaling pathway transduction and alleviated renal
ferroptosis and lipid peroxidation in hypertensive
state\textsuperscript{97}. It was also found that activation of Nrf2
inhibited the progression of hypertension in hypertensive mice 12-14
days after infusion of Ang II\textsuperscript{98} . At present, studies
on Nrf2 in the development and progression of hypertension are limited.
Whether Nrf2 can protect hypertension by regulating related mechanisms
to inhibit ferroptosis needs more research to determine.

It was also found that ferrostatin-1 administration could reverse the
ferroptosis of VSMCs induced by high hydrostatic
pressure\textsuperscript{7}, while also significantly ameliorating
hypertension and endothelial ferroptosis induced by lenvatinib in
mice\textsuperscript{13} . This suggests that ferrostatin-1 may
alleviate hypertension by inhibiting ferroptosis of VSMCs and
endothelial cells, but it has not been applied in the clinic so far, and
more in-depth and comprehensive research exploration of ferrostatin-1 is
needed to ensure its safety and efficacy.

Elabela (ELA) is a novel endogenous ligand of the Apelin receptor (APJ)
that regulates oxidative stress and plays a protective role in
cardiovascular and cerebrovascular diseases. Zhang et
al\textsuperscript{89}. found that ELA could significantly inhibit the
up-regulation of iron levels and lipid peroxidation in Ang II-induced
hypertensive mice. Further studies found that ELA inhibited cardiac
microvascular endothelial cell ferroptosis by regulating the
IL-6/STAT3/GPX4 signaling pathway. It has also been shown that ELA binds
to APJ and alleviates neuronal ferroptosis after ischemic stroke by
activating antioxidant signaling pathways\textsuperscript{99}. The above
studies suggest that ELA inhibition of the ferroptosis pathway has a
certain potential in the treatment of hypertension and cardiovascular
and cerebrovascular diseases, which needs further clinical and basic
experiments to verify.

\textbf{3.3.4 Iron overload in the brain caused by hypertension leads to
ferroptosis of neuronal cells}

Increased iron reserves in the body are associated with adverse outcomes
and symptomatic hypertension, and iron overload may offset the
beneficial effects of thrombolytic therapy\textsuperscript{100}. Yang et
al\textsuperscript{101}. found that elevated iron content, increased
lipid peroxide content, and changes in indicators related to ferroptosis
were found in the brain tissue of hypertensive rats compared with
normotensive rats, suggesting that hypertension may lead to brain iron
overload, and iron overload increases lipid peroxidation, thereby
inducing ferroptosis in neurons. This suggests that iron homeostasis
plays an important role in the development of hypertension. It has been
established that hypertension is the most common risk factor associated
with stroke because it puts pressure on the blood vessels of the brain,
resulting in hemodynamic changes that worsen clinical stroke
outcomes\textsuperscript{102,103}. However, how hypertension leads to
iron overload in the brain and what is the specific mechanism of
ferroptosis in hypertensive brain injury need further study and
discussion. As mentioned above, ferroptosis may play a key role in the
pathogenesis of hypertension and related brain damage, and inhibition of
ferroptosis may be a potential therapeutic target for the prevention and
treatment of hypertension and hypertensive heart and brain damage.
However, whether ferroptosis plays a key role in the impact of
hypertension on stroke severity and clinical outcome still needs further
study.

\textbf{3.4 Ferroptosis and diabetes mellitus}

Diabetes mellitus(DM) is a disease caused by insulin secretion
deficiency or insulin dysfunction, which leads to metabolic
abnormalities with chronic hyperglycemia as the prominent manifestation.
Diabetes mellitus is also another important risk factor for AIS and
increases the mortality and stroke recurrence rate associated with
it\textsuperscript{104,105}.

\selectlanguage{greek}\textbf{3.4.1 Ferroptosis may mediate islet β-cell dysfunction}\selectlanguage{english}

Islet beta cell dysfunction plays an important role in the occurrence
and development of diabetes. It has been proposed that pancreatic
\selectlanguage{greek}β-\selectlanguage{english}cells have low expression levels of the antioxidant enzymes superoxide
dismutase (SOD), glutathione (GSH) peroxidase, and
catalase\textsuperscript{106}, which suggests that they are susceptible
to oxidative stress and thus ferroptosis. Killion et
al\textsuperscript{107}. observed small atrophy of mitochondria,
increased membrane density, and disappearance of mitochondrial crista in
pancreatic islet \selectlanguage{greek}β \selectlanguage{english}cells of T2DM mice, and iron deposition in or near
the center of the islet, which was consistent with typical changes of
ferroptosis, further suggesting that ferroptosis may mediate the
dysfunction of pancreatic islet \selectlanguage{greek}β \selectlanguage{english}cells.When the iron homeostasis in
pancreatic \selectlanguage{greek}β \selectlanguage{english}cells is destroyed, a large amount of iron accumulates in
the cells. Excessive free reactive Fe2+ can produce lipid peroxides
through catalyzing lipid peroxidation, and form ROS through the Fenton
reaction. Due to the lack of antioxidant enzymes expressed by pancreatic
\selectlanguage{greek}β \selectlanguage{english}cells themselves, ROS and lipid peroxides cannot be eliminated in
time, and a large accumulation may cause ferroptosis. Make the islet
cell differentiation disorder and even death, resulting in reduced
insulin secretion. In vitro studies, erastin, an iron death inducer, was
associated with significantly reduced insulin secretion and impaired
islet function. Pretreatment with ferroptosis inhibitor ferrostatin-1 or
DFO rescued the above injury\textsuperscript{8}. These findings suggest
that ferroptosis may mediate islet \selectlanguage{greek}β-\selectlanguage{english}cell dysfunction.

\textbf{3.4.2 Ferroptosis may mediate insulin resistance}

ACSL4 is another important factor in the occurrence of ferroptosis, and
its increase will enhance lipid peroxidation and promote the production
of more lipid peroxides, finally leading to the ferroptosis of
cells\textsuperscript{108}. Up-regulation of ACSL4 expression was
observed in mice fed a high-fat diet(HD). In the same study,
adipocyte-specific ACSL4 knockout mice were found to be protected from
HD-induced cell death and insulin resistance\textsuperscript{109}.
Another experiment showed that ACSL4 protein is present in human and rat
islet \selectlanguage{greek}β \selectlanguage{english}cells, concentrated around insulin secretory granules and
mitochondria, and participates in insulin secretion by modifying fatty
acids in insulin secretory granules and
mitochondria\textsuperscript{110}. These findings suggest that ACSL4 may
promote insulin secretion in beta cells, but it may exacerbate
peripheral insulin resistance. Therefore, more experiments on the
function of ACSL4 are needed to explore whether ACSL4 mediates
ferroptosis and plays an important role in the pathogenesis of DM and
whether targeting ACSL4 can prevent and treat DM.

\textbf{3.4.3 Ferroptosis induced by hyperglycemia plays an important
role in the progression of diabetes and its complications}

Pancreatic \selectlanguage{greek}β-\selectlanguage{english}cell dysfunction and insulin resistance can lead to
hyperglycemia(HG), which can increase MDA levels in cells, reduce GPX4
activity\textsuperscript{111}, promote ferroptosis, and form a vicious
cycle. This vicious cycle accelerates the process of diabetes and its
complications. Previous studies have identified endothelial dysfunction
as one of the most important factors in vascular complications of
diabetes\textsuperscript{112}. Hyperglycemia-induced oxidative stress
and increased ROS production play an important role in the development
of endothelial dysfunction. It has been proposed that HG induces
ferroptosis in human umbilical vein endothelial cells (HUVECs),
accompanied by a significant increase in p53 in HUVECs, and p53 siRNA
and the use of ferroptosis inhibitors can attenuate HG-induced
ferroptosis in HUVECs\textsuperscript{113}. And studies show that in the
condition of diabetes, endothelial p53 expression raised obviously, and
endothelial-dependent vasodilation significant
damage\textsuperscript{114}. In an in vitro experiment mimicking
diabetic brain ischemic injury, Meg3 expression was found to be
increased, which could mediate p53 to cause ferroptosis by regulating
GPX4 transcription and expression. Knockdown of p53 protected rat brain
microvascular endothelial cells from ferroptosis induced by OGD +
hyperglycemic reperfusion, whereas overexpression of p53 produced the
opposite effect\textsuperscript{115}. A recent study showed that HG
intervention after MCAO aggravated neurological deficits, infarct size,
oxidative stress, iron accumulation, and BBB damage in a hemorrhagic
transformation model. Inhibition of P53 signaling attenuated ferroptosis
in the endothelium and reduced HG-induced hemorrhagic transformation
after MCAO\textsuperscript{116}. In conclusion, p53 may mediate
ferroptosis and play an important role in the progression of diabetes
and its complications, and inhibition of the p53 signaling pathway may
be a new therapeutic target for diabetes and its complications.
Together, these findings suggest that ferroptosis plays an important
role in the onset and progression of diabetes and its complications, and
therefore, the treatment and prevention of ferroptosis is a very
promising target for diabetes and its complications.

\textbf{3.5 Ferroptosis and obstructive sleep apnea}

Obstructive sleep apnea (OSA) has been associated with acute ischemic
stroke, hypertension, and atrial fibrillation\textsuperscript{117} . OSA
is considered an independent risk factor for recurrent
stroke\textsuperscript{118} . Its main pathophysiological feature is
chronic intermittent hypoxia (CIH)\textsuperscript{9}.

Intermittent hypoxia(IH) can induce ROS increase, lead to GSH depletion
through endoplasmic reticulum stress and affect GPX4
activity\textsuperscript{119}. Other studies have found that the levels
of Nrf2-ARE path-related antioxidant enzyme GPX4 in the peripheral blood
of patients with moderate to severe OSA are significantly reduced,
affecting the antioxidant capacity of the central nervous system,
resulting in an imbalance between oxidation and antioxidant, and
ultimately leading to neuron damage and signal transduction
abnormalities\textsuperscript{120}. Other studies have confirmed that
Nrf2 plays a protective role in the process of ferroptosis induced by
IH\textsuperscript{9,121}. This suggests that IH may affect the
expression of the antioxidant protein in the Nrf2-ARE pathway, resulting
in decreased expression of GPX4 and GSH in brain tissue, decreased
antioxidant capacity, increased expression of ROS and MDA, and lipid
peroxidation. In addition, elevated extracellular glutamate levels were
found in the brains of OSA patients\textsuperscript{122,123}. The
abnormal increase of extracellular glutamate level may lead to the
dysfunction of System Xc- transport, further inhibit the synthesis of
GSH, affect the ability to resist lipid peroxidation and promote
ferroptosis. Therefore, it can be inferred that ferroptosis may play an
important role in OSA-induced brain injury, and the mechanism may be
related to lipid peroxidation, abnormal increase of glutamate level, and
Nrf2 regulation disorder. However, there is still a lack of research on
OSA-mediated ferroptosis to promote the occurrence and progression of
AIS, which still has great potential.

\textbf{4. Conclusion and prospect}

The occurrence of cerebrovascular events is the result of many factors.
It is closely associated with various diseases, such as atherosclerosis,
atrial fibrillation, diabetes mellitus, hypertension, obstructive sleep
apnea, and so on. Comorbidities are the hallmark of stroke, which can
both increase the incidence of stroke and worsen the outcome. More and
more studies have shown that ferroptosis is not only involved in the
occurrence and progression of AIS but also involved in the chronic
pathogenesis of AIS risk factors.

This article mainly reviews the mechanism of ferroptosis in the
occurrence and development of acute ischemic stroke. By introducing the
relationship between ferroptosis and AS, AF, HF, DM, OSA, and the
specific mechanism of ferroptosis after acute ischemic stroke, it is
further explained that ferroptosis plays a very important role in the
occurrence and development of AIS. At the same time, the following
thoughts are also triggered: (1) Although this paper describes the
correlation between ferroptosis and AIS risk factors, the research on
the mechanism of ferroptosis and AIS risk factors is limited, and the
specific mechanism of ferroptosis is not clear, which is worthy of
further research by scientists. (2) Smoking, alcohol consumption, and
hyperlipidemia are also common risk factors for AIS. In future studies,
we can establish an acute ischemic stroke model in mice with AIS risk
factors, study the specific mechanism of neuronal ferroptosis, and find
targeted drugs and inhibitors to observe the impact on the prognosis and
treatment of AIS. (3) At least two or more types of programmed cell
death may occur in the occurrence and development of AIS. Therefore,
only targeting ferroptosis may not achieve the desired effect, and in
the future, multiple targets combined with cell death methods such as
apoptosis, autophagy, and necrosis can effectively treat the disease.
(4) So far, there is no clinical trial of inhibitors of ferroptosis for
the treatment of ischemic stroke. This field needs further exploration
and more population-based data are needed to determine whether the
prognosis of AIS patients can be improved by inhibiting ferroptosis.
With the deepening of research, inhibition of ferroptosis is likely to
become an effective strategy for the treatment of ischemic stroke.

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\textbf{Figure 1} Mechanism and regulation of ferroptosis in acute
ischemic stroke

Related regulatory mechanisms of iron metabolism: damage of the
blood-brain barrier, imbalance of iron transport, and NCOA4-mediated
ferritin autophagy can lead to iron overload and induce the Fenton
reaction to produce a large number of ROS. Lipid metabolism related
regulatory mechanisms: The increased expression of acyl-CoA synthetase
long-chain family member 4 (ACSL4) and lipoxygenases (LOXs) induced
lipid peroxidation. Amino acid metabolism related regulatory mechanisms:
The expression of solute carrier family 7 member 11(SLC7A11) was
inhibited and the synthesis of glutathione (GSH) was restricted. The
decreased content of glutathione peroxidase 4 (GPX4) eventually led to
excessive accumulation of lipid peroxide. Polyunsaturated fatty acids
(PUFAs); prostaglandin-endoperoxide synthase 2 (PTGS2); cyclooxygenase-2
(COX2); arachidonic acid (AA); adrenic acid (AdA);
lyso-phosphatidylcholine acyltransferase-3 (LPCAT3); lipid peroxide
(L-OOH); Phospholipids-H (L-OH); solute carrier family 3 member A2
(SLC3A2); glutathione- cysteine ligase (GCL); glutathione synthase
(GSS); oxidized glutathione (GSSH); transferrin (TF); transferrin
receptor1 (TFR1); Divalent metal transporter 1 (DMT1); Six-transmembrane
epithelial antigen of prostate 3 (STEAP3); labile iron pool (LIP);
ferroportin (FPN)

\textbf{Figure 2} Atherosclerosis associated ferroptosis hub gene

\emph{TP53} , \emph{MAPK1} , \emph{STAT3} , \emph{HMOX1} and
\emph{PTGS2}may be the key hub genes of AS-associated ferroptosis.

\textbf{Figure 3} Atrial fibrillation risk factors regulate ferroptosis
and affect atrial fibrillation susceptibility

Alcohol consumption, obesity, and sepsis are risk factors for atrial
fibrillation, which can participate in the regulation of ferroptosis and
affect the susceptibility to atrial fibrillation.

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