Cardiovascular diseases (CVDs), the leading cause of
death worldwide, claims ~18 million lives each year and has high
morbidity rates (1-4). Atherosclerosis is the main
pathologic mechanism of most CVDs (5). These chronic plaques in vessel,
composed mainly of cholesterol, fat, calcium and blood cells,
gradually harden over time, leading to arterial stenosis and
thereby restricting the flow of oxygen-rich blood to various parts
of the body (6). Atherosclerosis
has been found to be the central mechanism of this pathological
process and the leading cause of CVDs worldwide (7).
In recent years, atherosclerosis has been recognized
as a chronic inflammatory disease and leads to arterial stenosis
and plaque formation due to the accumulation of lipids and
inflammatory cells within the arterial wall (8-11). The role of adaptive immunity in
atherosclerosis has increasingly attracted attention (12). The adaptive immune system
participates in the development of atherosclerosis through various
cellular and molecular mechanisms, including the interactions of T
cells (13), B cells (14), antigen-presenting cells (15) and cytokines (16). Inflammation plays a key role in
the progression of atherosclerosis, and adaptive immune responses
influence plaque formation and stability by modulating the activity
of inflammatory cells and the secretion of cytokines. These studies
further confirm the key role of inflammation and immunity in
atherosclerosis and provide a theoretical basis for
immune-modulating therapies.
Epigenetics focuses on heritable changes in gene
expression that are not derived from alterations in the nucleotide
sequence, such as DNA or RNA methylation modifications, as well as
post-translational modifications of proteins (17). Lactylation, an emerging
post-translational modification, has garnered widespread attention
in biological and medical research (18-20). Lactylation plays a crucial role
in various biological processes, including the regulation of
macrophage function, modulation of glycolytic activity and the
promotion of tumorigenesis (21). As a key regulatory factor in
numerous biological processes and disease mechanisms, lactylation
modification has become a hot topic in molecular biology studies
(22,23).
Although the potential role of lactylation
modification in CVD has been demonstrated (24), its role in regulating immunity in
the context of atherosclerosis remains largely elusive. During the
pathological process of atherosclerosis, the accumulation of
lactate in local tissues obviously impacts this process. Therefore,
vast research efforts have explored the interaction between
lactylation modifications and adaptive immunity within the
atherosclerotic microenvironment. This review aims to clarify the
role of lactylation in immunity in the context of atherosclerosis
and summarize the driving mechanisms. This article not only
explores the roles of lactate and lactylation in atherosclerosis
but also systematically analyzes their impacts on various
components of the immune system, such as macrophages, T cells and B
cells. To the best of our knowledge, this multidimensional
perspective is relatively rare in previous reviews (12,25-27), as most studies have focused
solely on a single cell type or mechanism. By closely integrating
the metabolic characteristics of lactate with the regulation of
immune responses, the article highlights the crucial role of
metabolic reprogramming in atherosclerosis. This integrative
approach provides a more comprehensive framework for understanding
the pathogenesis of atherosclerosis. These innovative aspects not
only enrich our understanding of the pathogenic mechanisms of
atherosclerosis but also offer new directions for future
therapeutic strategies.
Lactate exists in two isomeric forms: D-lactate and
L-lactate, with L-lactate being the most common form in living
organisms (28). Lactate
transport mainly relies on monocarboxylate transporters (MCTs)
(29,30). In organisms, glucose is
metabolized to lactate via the glycolytic pathway under a short
supply of oxygen. Although only 2 ATP molecules are generated per
glucose molecule during this process, the energy output is
relatively low and the rapid production of lactate quickly provides
energy under hypoxic conditions to maintain normal cellular
functions (31). As an acidic
substance, lactate plays an important role in the acid-base balance
of the body. Furthermore, tumor cells often exhibit aerobic
glycolysis, producing large amounts of lactate even in the presence
of oxygen (32,33). This metabolic phenomenon is known
as the 'Warburg effect' and the accumulation of lactate facilitates
the growth and invasion of tumor cells (34,35).
Under normal physiological conditions, the
production and clearance of lactate are in a dynamic equilibrium.
It has been found that lactate is a metabolic byproduct of
glycolysis and an important signaling molecule (36-39). The metabolic pathways of lactate
vary with the cell type and environment. Lactate can be produced
through anaerobic glycolysis, leading to its accumulation, or it
can be oxidized to acetyl-coenzyme A (CoA) and enter the
tricarboxylic acid cycle (TCA) cycle during aerobic respiration
(40). Additionally, lactate can
be generated from pyruvate via the Warburg effect (41). These distinct metabolic fates
highlight the versatile roles of lactate in different physiological
contexts. For instance, in the immune system, lactate modulates the
activity of immune cells, inhibiting the overactivation of certain
immune cells while promoting the proliferation and differentiation
of others (42-44). In addition, lactate is involved
in various physiological and pathological processes as an energy
source and a signaling molecule and participate in epigenetic
modifications (e.g., lactylation) (19).
In the heart, lactate is a byproduct of glycolysis
and a key energy source for cardiomyocytes. Under normal
physiological conditions, lactate oxidation provides >50% of the
energy demands of cardiomyocytes. Even at rest, the proportion of
energy supplied by lactate oxidation can reach 10%, and during
exercise, this proportion can exceed 50% (45-47). Lactate enters the mitochondria
through the lactate oxidation complex, is converted into pyruvate,
and then enters the TCA cycle to ultimately generate ATP.
Furthermore, lactate activates a series of transcriptional
networks, affecting the expression and subcellular localization of
metabolism-related proteins in cardiomyocytes, such as
hexokinase-2, pyruvate kinase M2 (PKM2) and lactate dehydrogenase
A/B, thereby regulating metabolic homeostasis in cardiomyocytes
(48-52). Lactate and pyruvate can also
scavenge free radicals, protecting cardiomyocytes from oxidative
stress damage (53-55). A cross-sectional study involving
1,496 participants reported that blood lactate levels were
independently associated with carotid atherosclerosis, suggesting
that lactate is involved in atherosclerosis development (56). During the progression of
atherosclerosis, lactic acid accumulates in the microenvironment of
atherosclerotic plaques as an end product of glycolysis and leads
to local acidification. This acidic microenvironment facilitates
the binding of oxidized low-density lipoprotein (oxLDL) to aortic
proteoglycans, triggers local immune responses and recruits immune
cells, thereby exacerbating inflammatory reactions (57). Furthermore, lactic acid
stabilizes hypoxia-inducible factor 1α (HIF-1α) and N-myc
downstream regulated gene 3. This further promotes the expression
of pro-angiogenic factors such as vascular endothelial growth
factor and forms a positive feedback loop that promotes
atherosclerosis development (58) (Fig. 1).
Lactate participates in cellular metabolism to
provide energy, serves as a donor for lactylation modification and
contribute to the regulation of the local tissue
microenvironment.
Atherosclerosis is a chronic inflammatory disease
triggered by lipid metabolism disorders and characterized by the
formation of atherosclerotic plaques beneath the intima of large
and medium-sized arteries (5,11,12). During the progression of
atherosclerosis, the glycolysis levels of cells within the plaque
significantly increase, leading to excessive production and release
of lactic acid, which in turn acidifies the extracellular
environment (59-61). This metabolic change further
influences the development of atherosclerosis through multiple
mechanisms.
There is a close and complex interrelationship
between atherosclerosis and the immune system (25,62,63). As a chronic inflammatory disease,
the inflammatory process in atherosclerosis is typically initiated
by the deposition of oxLDL and damage to endothelial cells. After
endothelial injury, cytokines and chemokines are released as
inflammatory mediators and then attract monocytes and other
inflammatory cells into the vascular wall, thereby initiating the
inflammatory response (Fig. 2)
(64). The immune system plays a
critical role in atherosclerosis through the interplay of innate
and adaptive immune responses, immune cell metabolism and cytokine
networks, driving inflammation and plaque progression.
The involvement of various immune cells plays a
crucial role in atherosclerosis. Macrophages engulf oxLDL to form
foam cells that accumulate within the vascular wall and serve as
the foundation for plaque formation (65-67). Lipidomics and transcriptomics
analyses have shown that foam cells themselves do not possess
pro-inflammatory properties. However, the increased oxidative
stress in the arterial wall and the accumulation of modified
lipoproteins reprogram the metabolic processes of macrophages,
thereby triggering inflammatory responses that promote
atherosclerosis (68,69). After cell death, lipid-overloaded
macrophages are usually phagocytized by other macrophages (70). However, when phagocytic cells
become overwhelmed, they release pro-inflammatory components. The
retention of macrophages in the arterial wall is promoted by
adhesion molecules (e.g., vascular cell adhesion molecule 1) and
neuroguidance factors (such as netrin 1), while high-density
lipoprotein facilitates the egress of macrophages from plaques
through a C-C motif chemokine receptor (CCR)7-mediated mechanism
(71-74). Macrophages in atherosclerotic
plaques exhibit pro-inflammatory or anti-inflammatory
characteristics but do not follow the classical M1/M2
classification (25,75). Single-cell studies have
identified at least five distinct macrophage subpopulations in the
mouse aorta, including inflammatory macrophages, type I
interferon-inducible cells, foam cells with high expression of
triggering receptor expressed on myeloid cells 2, aortic
intima-resident macrophages and embryonic-derived resident
macrophages (68,69,76,77). These subpopulations play diverse
roles in atherosclerosis. These cells exert both pro-inflammatory
and anti-inflammatory effects during disease progression and their
functions are regulated by multiple factors, such as cholesterol
metabolism, oxidative stress and cell-to-cell interactions. Efforts
should be invested to further characterize the functions of these
macrophage subpopulations and explore their specific mechanisms of
action in atherosclerosis.
Adaptive immunity is a key modulator of
atherosclerosis. T cells play a complex role in atherosclerosis and
different subsets influence disease progression through numerous
mechanisms. Type 1 T-helper (Th1) cells are the most prominent
CD4+T-cell subset in atherosclerotic plaques, promoting
lesion development and plaque instability by secreting IFNγ and
expressing T-bet (78,79). The mechanisms include inducing
the uptake of oxLDL, foam cell formation, polarization of
macrophages to a pro-inflammatory phenotype and proliferation of
vascular smooth muscle cells (13,80,81).
The role of Th17 cells in atherosclerosis remains
controversial. In mouse models, the number of T cells expressing
IL-17 is positively correlated with atherosclerosis. Depletion of
Th17 cells inhibits the production of pro-inflammatory cytokines
and chemokines, as well as leukocyte infiltration and plaque
formation (92). In addition to
its pro-inflammatory effects, IL-17A has a plaque-stabilizing role
in atherosclerosis (93).
Neutrophils are mainly associated with events
following plaque rupture or erosion, releasing various enzymes and
cytokines that participate in the inflammatory response and tissue
repair process (105-107). NK cells modulate the activity
of other immune cells by releasing cytokines and cytotoxic
granules, thereby influencing the immune response within
atherosclerotic plaques (108).
Mast cells, primarily located in the adventitia of arteries,
release histamine, enzymes and cytokines, degrade the extracellular
matrix, promote the further recruitment of inflammatory cells and
enhance local inflammation, increasing the complexity and potential
rupture risk of atherosclerotic plaques (109,110) (Table I).
During the progression of atherosclerosis, the
persistent inflammatory response significantly impacts the immune
system. Chronic inflammation can lead to overactivation or
dysfunction of the immune system, thus increasing the risk of
autoimmune diseases. Furthermore, vascular changes caused by
atherosclerosis can affect the transport and distribution of immune
cells, thereby influencing the normal function of the immune system
(111-113). Considering the close
relationship between atherosclerosis and the immune system, immune
regulation strategies have potential in treating atherosclerosis.
By modulating the function of immune cells, inhibiting the
production of pro-inflammatory cytokines or enhancing the effects
of anti-inflammatory cytokines, it is possible to reduce the
inflammatory response, stabilize atherosclerotic plaques and
thereby reduce the risk of cardiovascular events, offering new
potential therapeutic options for atherosclerosis.
Lactylation is an epigenetic modification that
involves post-translational modifications of both histone and
non-histone proteins and plays a key role in the regulation of gene
transcription and protein function (114). There are three isomers
generated in this process: Lysine L-lactylation (Kl-la),
N-ε-(carboxyethyl) lysine and D-lactyl lysine. It has been shown
that Kl-la is the primary form of lactylation within cells and
significantly contributes to glycolysis and the Warburg effect
(115). Lactylation tends to
occur at nucleophilic sites, such as amino groups
(-NH2), interacting with corresponding functional
groups, and this high level of selectivity allows lactylation to
precisely target specific proteins, causing significant changes in
their properties and functions (114) (Fig. 3).
Induced by the accumulation of lactate, lactylation
modifies proteins and alters the spatial conformation of histones,
thereby affecting gene transcription and the regulation of gene
expression. Similarly, it affects the function of non-histone
proteins by altering their spatial conformation. Lactylation
involves a series of enzyme-catalyzed, reversible chemical
reactions, rather than spontaneous chemical activity (116). The 'writers' of lactylation
refer to enzymes or proteins capable of catalyzing lactylation
reactions, transferring lactoyl groups to target proteins after
lactate is converted into lactoyl-CoA. The known lactylation
'writers' proteins mainly include histone acetyltransferases
Sirtuin (SIRT)1 (117), P300
(117), lysine
acetyltransferase 2A (KAT2A) (118), Tat-interactive protein 60 kDa
(119,120) and KAT8 (121,122). 'Erasers' include enzymes or
proteins that remove or erase lactoyl groups through hydrolysis,
restoring the target molecule to its original state, with histone
deacetylases (123) and SIRTs
(124,125) being known 'erasers' that remove
lactylation modifications. In biology, 'readers' are defined as
proteins or domains capable of recognizing and interacting with
lactoyl groups. Although no specific lactylation readers have been
discovered, this may be related to the recent discovery of
lactylation and an incomplete understanding of its underlying
molecular mechanisms. Lactylation, a post-translational
modification first reported in 2019 by Professor Yingming Zhao's
group at the University of Chicago, has a shorter research history
compared to classical modifications like acetylation and
phosphorylation (19). Although
the identification of specific 'reader' proteins for lactylation is
still in progress, their functional roles have been confirmed
through various studies. For instance, histone H3K18 lactylation
influences macrophage polarization and tumor microenvironment
regulation (126), lactylation
of cyclic GMP-AMP synthase inhibits its immune activity, and
lactylation in NK cells causes mitochondrial dysfunction (127). The lack of identified 'readers'
does not diminish lactylation's biological significance but rather
highlights the field's rapid development. Current evidence
underscores its crucial roles in gene regulation, immune responses
and disease. Future technological advancements and in-depth
research are expected to uncover lactylation-specific 'readers',
further clarifying its molecular mechanisms. As research
progresses, more information about lactylation readers will be
revealed in the future, leading to a more comprehensive
understanding of the molecular mechanisms of lactylation.
Lactylation is an important epigenetic modification
mechanism that plays a key role in various physiological and
pathological processes by affecting protein stability, enzyme
activity, protein-protein interactions, protein distribution,
structure and function (128).
Specifically, lactylation involves a series of complex
physiological activities, including somatic cell reprogramming
(129,130), embryonic development (131-133), neural excitation (134), osteoblast differentiation
(135,136), pyroptosis (137,138), macroautophagy (139), decidualization (140), homologous recombination
(119,141), cuproptosis (142), myogenesis (143) and oxidative phosphorylation
(52,144). In addition, lactylation is
closely related to the occurrence and development of various
diseases, including but not limited to malignant tumors (22,119), inflammation-related diseases
(145-147), fibrosis-related diseases
(148,149), Alzheimer's disease (150), heart disease (60,117,151), insulin resistance (152), nonalcoholic fatty liver disease
(153), cerebral infarction
(154,155), viral infections (156,157) and endometriosis (158).
In atherosclerotic plaques, high concentrations of
lactate induce metabolic reprogramming in macrophages, shifting
their metabolism from glycolysis to oxidative phosphorylation
(159-161). This metabolic remodeling
significantly impacts the functional status of macrophages: The
accumulation of lactate inhibits mitochondrial function, reduces
ATP production and consequently diminishes the activity and
functional performance of macrophages (111,162,163). Furthermore, lactate induces the
polarization of macrophages towards the M2 phenotype while
inhibiting M1 polarization, thereby promoting their
anti-inflammatory and immunosuppressive functions (164,165). Besides, lactate attenuates
inflammatory responses by reducing the phosphorylation levels of
NF-κB, thereby suppressing the transcription of
inflammation-related genes (166).
More critically, lactate can induce histone
lactylation, a modification that regulates macrophage metabolism
and phenotypic transformation by acting on both histones (such as
H3K18la) and non-histone proteins (such as PKM2) (167-169). For instance, H3K18la
modification activates the expression of M2-related genes and
drives the transformation of M1 macrophages towards the M2
phenotype. Macrophage activation is one of the key features of
atherosclerosis, typically accompanied by a shift in core
metabolism from oxidative phosphorylation to glycolysis (19). It has been found that histone
lactylation mediated by MCT4, which is associated with lactate
efflux, is closely related to atherosclerosis. In the absence of
MCT4, histone lactylation at lysine 18 of histone H3 activates the
transcription of anti-inflammatory and TCA cycle genes, thereby
initiating local repair and homeostasis (170). This finding indicates that
lactylation plays an important role in regulating macrophage
function and the progression of atherosclerosis.
Lactate is a byproduct of glycolysis and usually
accumulates in large amounts in the tumor microenvironment,
creating an acidic ecological niche. In the acute inflammatory
phase, lactate primarily exerts anti-inflammatory effects by
activating the G protein-coupled receptor 81 receptor, thereby
inhibiting the production of inflammatory mediators and alleviating
the inflammatory response (171,172). However, the acidic environment
caused by lactate accumulation exacerbates the persistence of
inflammation and promotes tissue damage in the chronic inflammatory
phase. Nevertheless, lactate also induces the polarization of
immune cells and modulates metabolic pathways to facilitate the
resolution of inflammation and exert certain anti-inflammatory
effects (173,174).
The activation and differentiation of T cells are
accompanied by metabolic reprogramming, one of the metabolic
hallmarks being aerobic glycolysis, which refers to the conversion
of glucose to lactate in the presence of oxygen (175). T cells undergo metabolic
reprogramming in different states of differentiation (176). For instance, effector T cells
primarily rely on glycolysis, whereas regulatory T cells and memory
T cells mainly depend on oxidative phosphorylation (177,178). T cells sense lactate through
the expression of specific transporters, which leads to the
inhibition of their migratory capacity. This 'stop signal' for
migration depends on the interference of lactate with intracellular
metabolic pathways, particularly glycolysis. Lactate promotes the
differentiation of CD4+ T cells into the IL-17+ subset while
reducing the cytotoxic capacity of CD8+ T cells. These phenomena
lead to the formation of ectopic lymphoid structures at sites of
inflammation and the production of autoantibodies (43,179). Lactate triggers the nuclear
translocation of the PKM2 via an active transmembrane influx
mediated by the sodium-coupled monocarboxylate transporter 2 (also
known as solute carrier family 5 member 12). Within the nucleus,
PKM2 forms a complex with phosphorylated signal transducer and
activator of transcription 3, synergistically enhancing the
transcriptional activity of the IL-17 gene, thereby markedly
promoting IL-17 secretion by Th17 cells (180-182). The activity of Tregs relies on
the metabolic reprogramming from glycolysis to oxidative
phosphorylation, a process strictly regulated by the transcription
factor forkhead box P3. Lactate promotes the accumulation of Tregs
at inflammatory sites and activates the HIF-1α-dependent CCL20/CCR6
signaling axis, facilitating Treg migration to the lesion area. In
addition, Tregs utilize lactate as a substrate for the TCA cycle,
further enhancing their immunosuppressive function (164,183,184). Nevertheless, in chronic
inflammatory responses, the persistent accumulation of lactate
causes local tissue damage and drives the progression of chronic
inflammation, which significantly exacerbates the pathological
impact on atherosclerotic lesions and accelerates disease
progression (173,179). Lactate plays a complex dual
role in inflammation and immune responses. It exerts
anti-inflammatory effects by regulating metabolism and immune cell
functions, but it exacerbates tissue damage and disease progression
in chronic inflammation.
Lactylation promotes Th17 differentiation and
participates in the development of autoimmune diseases and
inflammatory responses by regulating site-specific modifications of
key proteins such as IKAROS family zinc finger 1, which directly
modulates the expression of Th17-related genes (185). In the tumor microenvironment,
lactate regulates the generation of Treg cells through lactylation
modification at lysine 72 of the MOESIN protein. This process
enhances the interaction between MOESIN and transforming growth
factor-β receptor I, activates the downstream SMAD3 signaling
pathway and significantly improves the stability and function of
Treg cells (186). This
discovery provides an important reference for understanding the
regulatory mechanisms of lactate accumulation on Treg cells in the
context of atherosclerotic tissue environments.
Lactate significantly inhibits the proliferation
capacity and antibody production of B cells by reducing the
extracellular pH (159,187). Additionally, lactate modulates
the metabolic pathways of B cells, particularly by enhancing the
glycolytic process, which provides rapid energy supply to support
their proliferation and differentiation. At the same time, lactate
suppresses oxidative phosphorylation and results in significant
alterations in the metabolic state of B cells (28,188). At the molecular level, lactate
promotes the growth and metabolic activities of B cells by
activating the mammalian target of rapamycin signaling pathway
(189,190). Under hypoxic conditions,
lactate enhances the adaptability of B cells to low oxygen
environments by stabilizing HIF-1α (191-193). Furthermore, lactate activates
the NF-κB signaling pathway, promoting the secretion of
pro-inflammatory cytokines by B cells, thereby participating in the
regulation of inflammatory responses (194,195). These findings demonstrate that
lactate plays a multifaceted role in the functional regulation of B
cells, influencing metabolic reprogramming, signaling pathway
activation and environmental adaptability, among other aspects.
Lactylation modulates the antibody class switch recombination (CSR)
in B cells by influencing metabolic pathways. For instance, the
MCT1-mediated lactate transport and pyruvate metabolism regulates
the acetylation modification of histone H3K27, thereby affecting
the transcriptional efficiency of activation-induced cytidine
deaminase, which ultimately impacts the CSR in B cells (196) (Fig. 4).
Lactate and its mediated lactylation modifications
play a complex dual role in atherosclerosis by regulating metabolic
reprogramming, functional polarization and epigenetic modifications
of macrophages, T cells and B cells.
In summary, this review comprehensively analyzes the
multifaceted roles of lactate and lactylation in shaping the immune
system within the context of atherosclerosis. As a chronic
inflammatory disease, atherosclerosis is characterized by the
complex interplay between lipid metabolism, immune cell
infiltration and the local microenvironment. The results highlight
the critical roles of lactate and lactylation in modulating immune
cell functions, metabolic reprogramming and epigenetic regulation,
thereby influencing the progression and stability of
atherosclerotic plaques.
The involvement of lactate and lactylation in the
regulation of macrophage polarization, T cell differentiation and B
cell metabolism underscores their potential as therapeutic targets.
Specifically, lactate-induced metabolic reprogramming and
lactylation modifications have been shown to significantly impact
the phenotypes and functions of immune cells and contribute to
pro-inflammatory and anti-inflammatory responses. These insights
provide a deeper understanding of the immune metabolic mechanisms
underlying atherosclerosis and pave the way for novel therapeutic
strategies targeting lactate metabolism and lactylation
pathways.
However, despite the progress made in elucidating
the roles of lactate and lactylation in atherosclerosis, several
gaps remain in our knowledge. The complex microenvironment of
atherosclerotic plaques, characterized by hypoxia, nutrient
deprivation and acidosis, is likely to influence the behavior of
immune cells and the efficacy of potential treatments. Yet, the
precise mechanisms through which these microenvironmental factors
interact with lactate and lactylation to modulate immune responses
are still not fully understood. Additionally, the diverse metabolic
profiles and functional states of immune cells within plaques
suggest that a more detailed characterization of immune cell
subsets and their specific roles is needed.
Furthermore, the dynamic changes in the
atherosclerotic microenvironment over time, from plaque initiation
to rupture, add another layer of complexity to the study of immune
regulation. The impact of these temporal changes on lactate
production, lactylation modifications and immune cell function
remains elusive. Furthermore, the potential compensatory mechanisms
and feedback loops involving other metabolic pathways and
epigenetic modifications in response to lactate accumulation and
lactylation need further investigation.
In conclusion, although significant advancements
have been made in understanding the roles of lactate and
lactylation in atherosclerosis, the intricate interplay between the
microenvironment, metabolic changes and immune regulation remains
an area of considerable research need. Future studies should focus
on unraveling the detailed mechanisms through which the
atherosclerotic microenvironment influences lactate metabolism and
lactylation, as well as their downstream effects on immune cell
function. These will enhance our understanding of the
pathophysiology of atherosclerosis and provide new avenues for
developing targeted therapies aimed at modulating immune responses
and improving clinical outcomes.
Not applicable.
YX was involved in the conceptualization of the
review, data curation, investigation, methodology and
writing-original draft. JZ was responsible for data curation and
project administration. JW contributed to the conceptualization,
data curation and methodology. HH was involved in
conceptualization, data curation, investigation, methodology and
writing-original draft, writing-review & editing. All authors
have read and approved the final manuscript. Data authentication is
not applicable.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
Not applicable.
No funding was received.
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