Iron accumulation and lipid peroxidation: implication of ferroptosis in diabetic cardiomyopathy

Abstract

Diabetic cardiomyopathy (DC) is a serious heart disease caused by diabetes. It is unrelated to hypertension and coronary artery disease and can lead to heart insufficiency, heart failure and even death. Currently, the pathogenesis of DC is unclear, and clinical intervention is mainly symptomatic therapy and lacks effective intervention objectives. Iron overdose mediated cell death, also known as ferroptosis, is widely present in the physiological and pathological processes of diabetes and DC. Iron is a key trace element in the human body, regulating the metabolism of glucose and lipids, oxidative stress and inflammation, and other biological processes. Excessive iron accumulation can lead to the imbalance of the antioxidant system in DC and activate and aggravate pathological processes such as excessive autophagy and mitochondrial dysfunction, resulting in a chain reaction and accelerating myocardial and microvascular damage. In-depth understanding of the regulating mechanisms of iron metabolism and ferroptosis in cardiovascular vessels can help improve DC management. Therefore, in this review, we summarize the relationship between ferroptosis and the pathogenesis of DC, as well as potential intervention targets, and discuss and analyze the limitations and future development prospects of these targets.

Full text

Yanetal. Diabetology & Metabolic Syndrome (2023) 15:161
https://doi.org/10.1186/s13098-023-01135-5
REVIEW Open Access
© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or
other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this
licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco
mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Diabetology &
Metabolic Syndrome
Iron accumulation andlipid peroxidation:
implication offerroptosis indiabetic
cardiomyopathy
Xuehua Yan1,2, Yang Xie3, Hongbing Liu1, Meng Huang1, Zhen Yang1, Dongqing An1,2,3* and Guangjian Jiang1*
Abstract
Diabetic cardiomyopathy (DC) is a serious heart disease caused by diabetes. It is unrelated to hypertension and coro-
nary artery disease and can lead to heart insufficiency, heart failure and even death. Currently, the pathogenesis
of DC is unclear, and clinical intervention is mainly symptomatic therapy and lacks effective intervention objectives.
Iron overdose mediated cell death, also known as ferroptosis, is widely present in the physiological and pathologi-
cal processes of diabetes and DC. Iron is a key trace element in the human body, regulating the metabolism of glu-
cose and lipids, oxidative stress and inflammation, and other biological processes. Excessive iron accumulation can
lead to the imbalance of the antioxidant system in DC and activate and aggravate pathological processes such
as excessive autophagy and mitochondrial dysfunction, resulting in a chain reaction and accelerating myocardial
and microvascular damage. In-depth understanding of the regulating mechanisms of iron metabolism and ferroptosis
in cardiovascular vessels can help improve DC management. Therefore, in this review, we summarize the relationship
between ferroptosis and the pathogenesis of DC, as well as potential intervention targets, and discuss and analyze
the limitations and future development prospects of these targets.
Keywords Ferroptosis, Lipid peroxidation, Diabetic cardiomyopathy, Diabetes
Introduction
Diabetic cardiomyopathy (DC) is a common diabetic car-
diovascular complication of ventricular insufficiency in
diabetic patients in the absence of coronary atherosclero-
sis and hypertension [1]. DC can occur in both type 1 and
type 2 diabetes mellitus [2]. e occurrence and devel-
opment of DC are associated with hyperglycemia [3],
insulin resistance [4], mitochondrial dysfunction [5, 6],
reactive oxygen species (ROS) accumulation [7], micro-
vascular dysfunction [8] and other factors are closely
related. So far, although the above factors have provided
the direction for the pathogenesis of DC, the exact patho-
genesis of DC is still unclear. In addition to strict con-
trol of blood glucose [9], using the traditional and novel
hypoglycemic drugs [10, 11], there is still a lack of inter-
vention for the REDOX imbalance caused by the disorder
of glucose and lipid metabolism and iron metabolism, at
present, and the targeted intervention for the pathogen-
esis of DC needs further research.
Recent studies have shown that ferroptosis is essential
in the pathogenesis of DC [12–15]. Iron overload may
promote the introduction of polyunsaturated fatty acids
into the cell membrane, leading to an excessive accu-
mulation of lipid hydroperoxides and an imbalance of
*Correspondence:
Dongqing An
326468701@qq.com
Guangjian Jiang
bucmjiang@163.com
1 College of Traditional Chinese Medicine, Xinjiang Medical University,
Xinjiang, China
2 Xinjiang Key Laboratory of Famous Prescription and Science
of Formulas, Xinjiang, China
3 Affiliated Hospital of Traditional Chinese Medicine of Xinjiang Medical
University, Xinjiang, China
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 2 of 16
Yanetal. Diabetology & Metabolic Syndrome (2023) 15:161
REDOX [16, 17], thus mediating regulatory cell death, i.e.
ferroptosis. Wang etal. [12] confirmed the real existence
of ferroptosis in cardiomyocytes of DC and its damaging
effect on the heart by invivo and invitro experiments,
respectively. In the invitro experiment, the expression of
lipid peroxidation marker malondialdehyde and ferrop-
tosis marker Ptgs2 in DC cardiomyocytes was increased,
and the expression of SLC7A11, glutathione (GSH) level
and ferritin level were decreased. Moreover, the typical
ferroptosis morphological changes of DC mouse car-
diomyocytes were confirmed by transmission electron
microscopy [12], which further confirmed the destructive
effect of ferroptosis on the structure and function of car-
diomyocytes, and emphasized the important significance
of ferroptosis in the myocardial injury of DC [12, 18].
Early studies have found that myocardial apoptosis
expressed in diabetic tissues is 85 times that in non-dia-
betic tissues [19, 20]. Jinjing etal. [21] pointed out that
there are various forms of cell death in DC, and inhibiting
any form of cardiac cell death will have a huge protective
effect on DC. A number of experiments have confirmed
this view, namely, inhibiting ferroptosis is beneficial to
reducing myocardial injury [22–24], effectively prevent-
ing cardiomyocytes and improve cardiac dysfunction
[12, 24], and delaying the progression of DC. Inhibiting
ferroptosis provides a new research direction for clini-
cal intervention of DC. Applying iron chelating agents
reduced the level of oxidation stress, inflammation, and
myocardial remodeling [25, 26]. However, the current
research on iron death in DC is still limited to animal
experiments and cell experiments, and the research and
understanding of human beings are still very limited.
erefore, we summarized iron metabolism, lipid
metabolism and ferroptosis related signaling pathways,
analyzed and discussed the related cellular and molecu-
lar mechanisms of ferroptosis in myocardial injury and
microvascular injury of DC. e potential intervention
targets and future research prospects of ferroptosis in
DC are comprehensively discussed, which provides a new
research direction for the clinical diagnosis and treat-
ment of DC.
Molecular mechanism offerroptosis
Unlike other programmed apoptosis mechanisms, fer-
roptosis is specific in genetics, morphology, immunol-
ogy, and biochemistry, as shown in Table1. Ferroptosis
is closely related to iron metabolism, amino acid metabo-
lism, lipid metabolism and other metabolic pathways, as
shown in Fig.1. erefore, this part focuses on introduc-
ing the pathogenesis of DC mediated by ferroptosis under
the action of the above molecular metabolic pathways.
Iron metabolism
One of the vital trace elements in the human body is iron.
On the one hand, as a cofactor, in the form of reduced
state (Fe2+), iron is widely involved in the synthesis of
human DNA, iron-sulfur clusters and hemoglobin [41,
42], regulating the activities of lipoxygenase, mitochon-
drial complex I and II and other enzymes [43, 44], and
regulating the proliferation and differentiation of cells.
On the other side, through the Fenton reaction, iron
can also result in the creation of poisonous oxygen free
radicals (hydroxyl radicals). erefore, iron metabolism
needs to be tightly regulated at the cellular and biologi-
cal levels. Dietary iron intake can be absorbed into intes-
tinal cells in four ways: part of iron ions are absorbed
into cells by heme carrier protein 1 transporter (HCP1)
on duodenal intestinal cells [45, 46], or dietary ferritin
is absorbed into intestinal cells by some entosis mecha-
nism [47]. Low PH in the stomach or ascorbic acid can
decrease the remaining Fe3+ bound to citrate to Fe2+. In
addition, duodenal cytochrome b (Dcytb) and prostatic
6 transmembrane epithelial antigen 2 (STEAP2) proteins
on the top membrane of intestinal cells can use ascorbic
acid oxidation to reduce Fe3+ to Fe2+. Reduced Fe2+ is
transported into intestinal cells via divalent metal trans-
porter 1 (DMT1, also known as Nramp2, SLC11A2, and
DCT1) or zinc transporter Zrt-Irt‐like proteins 14 and
8 (ZIP 14/8) [48–50]. Heme can be broken down inside
the cell or taken into the bloodstream, and heme oxyge-
nase (HO1) can break down the heme groups to liberate
free iron (Fe2+). Intracellular iron regulation is strictly
dependent on the REDOX state (Fe2+/Fe3+) and is usu-
ally stored as a protein in the oxidized state of Fe3+ in
the unstable iron cisterna (LIP) [51, 52] or through the
cytoplasmic transport of ferritin 1 (FPN1, Also known
as MTP1, IREG1 and SLC40A1) are transported to the
extracellular blood [53] and transported to the circula-
tory system by the liver transport protein transferrin (TF)
[54].
Several important regulators affect the intracellular
iron content and homeostasis. NRF2 is a key regulator of
cellular oxidation stability, encoded by the NFE2L2 gene
and belonging to the leucine zipper structure family [55].
Genes associated to iron excess and lipid peroxidation are
also NRF2 target genes [56]. NRF2 controls the transcrip-
tion of the iron metabolism-related gene SLC40A1 in the
nucleus [57]. NRF2, a crucial transcription factor for pre-
serving oxidative homeostasis, is activated by severe oxi-
dative stress to encourage the transcription of the target
genes GPX4, HO-1, and SLC7A11 [58, 59]. By control-
ling the production of iron metabolism-related proteins,
transcription modification after interlinking iron regula-
tory proteins (IRPs) and iron response elements (IREs)
is engaged in the regulation of cellular iron homeostasis
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 3 of 16
Yanetal. Diabetology & Metabolic Syndrome (2023) 15:161
Table 1 Type of cell death
Type of cell death Denition Feature and regulation Disease References
Autophagy Removes abnormal proteins and orga-
nelles and maintains cell homeostasis
by removing misfolded proteins
and damaged organelles and invading
microorganisms through lysosomes
A large vacuole of the cytoplasm, the formation of autophagosomes, phagocyto-
sis and subsequent lysosomal degradation Infection; immune disease; metabolic
disease; cancer; neurodegenerative [27, 28]
Apoptosis Citing no inflammatory responses regu-
lated by genes, which plays important
roles in maintain cells stability in tissues,
immune and defense responses,
growth and development of tumors,
and cells damage caused by poisoning
The contraction of cytoplasm, shrinkage of the nucleus, rupture of the nucleus,
fragmentation of DNA, foaming of plasma membranes, and formation of apop-
tosis bodies
Cancer; atherosclerosis, diabetes;
hepatic fibrosis; wound healing [29, 30]
Necroptosis A type of regulated necrosis that criti-
cally depends on RIPK3 and MLKL Organelles and plasma membrane rupture, and the final treated cell cadavers
were not obviously involved in phagocytes and lysosomes Viral infection; acute kidney injury;
cardiac ischemia/reperfusion; human
tumors
[31]
Ferroptosis A form of cell death driven by iron-
dependent lipid peroxidation Genetics Regulated by multiple genes, mainly
the changes of iron homeostasis
and lipid peroxidation genes
Aging; immunity; cancer; cardiovascu-
lar diseases; ischemic-reperfusion [32, 33]
Morphology The mitochondrial volume decreased,
the density of double-layer structure
increased, the crest decreased or disap-
peared
Immunology Injury-related molecular pattern mol-
ecules release inflammatory mediators
to trigger inflammatory response
Biochemistry GSH consumption, GPX4 activ-
ity decreased, Fe2+ mediated lipid
peroxidation through Fenton reaction,
produce excess ROS
Cuproptosis Copper directly binds to lipoylated
components of the tricarboxylic acid
(TCA) cycle, causing protein aggrega-
tion, iron-sulfur cluster protein loss,
proteotoxic stress, and cell death
The key regulators: FDX1 and protein lipoylation Wilson’s; Alzheimer’s disease; Parkin-
son’s disease [34–36]
Function channel: Mitochondrial respiration
Upstream regulator FDX1
Pyroptosis A form of programmed cell death
mediated by the N-terminal fragment
of gasdermin D that gives rise to inflam-
mation via the release of some proin-
flammatory cytokines, including IL-1β,
IL-18 and HMGB1
The canonical signalling pathway dependent on caspas-1 and the non-canonical
signalling pathway determined by caspas-4/5/11 Fibrosis; Kidney disease; atherosclerosis;
diabetes; neurodegenerative diseases; [37–40]
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 4 of 16
Yanetal. Diabetology & Metabolic Syndrome (2023) 15:161
[60]. In addition, to further reduce the intracellular iron
production of transferrin, ferriophagy can control the
nuclear receptor coactivator 4 (NCOA4) intracellular
iron regulator. Iron-responsive element-binding protein 2
(IREB2), another important encoder, primarily influences
transferrin expression and iron transport [61].
e control of iron homeostasis can be achieved by
post-transcriptional regulation in addition to transcrip-
tional regulation. According to a study, FPN1 expres-
sion is reduced in NRF2 knockout mice [62]. FPN1 is the
only iron-release related protein discovered in mammals,
and it is encoded by the SLC40A1 gene [63]. It is impor-
tant for systemic iron homeostasis. Recent research has
revealed that altering NRF2 expression in the nucleus
can influence its transcriptional target FPN1, resulting
in decreased iron outflow and increased intracellular
iron accumulation [64]. During myocardial cell injury,
NRF2 is transferred from the cytoplasm to the nucleus,
thereby activating the transcription of its target gene
FPN1 to limit iron ptosis. Low expression of FPN1 exac-
erbates iron ptosis and intracellular iron buildup in dia-
betic heart disease. However, in diabetic rats, activation
of NRF2 overexpression can greatly increase the tran-
scription of FPN1 and minimize myocardial damage [65].
Different from the whole-body iron regulation pathway,
iron metabolism in cardiomyocytes is mainly through
the secretion function of the heart itself to promote the
up-regulation of cardiac iron modulin protein to achieve
iron homeostasis [66]. It may thus be more evidence that
cardiomyocytes are more susceptible to iron overload
than other cell types as only the FPN protein is accessible
for iron output during iron accumulation.
System XC−/GSH/GPX4 pathway
e fundamental cause of ferroptosis is an unbalanced
cellular antioxidant defense system, namely the inac-
tivation of the XC-GSH-GPX4-dependent antioxi-
dant defense system, which leads to the buildup of lipid
hydroperoxide. ROS antagonism relies on the biosynthe-
sis of GSH, which is introduced or sulfurized by cystine,
and selenium, which is essential for the proper function-
ing of GPX4. e system XC- consists of two subunits,
SLC7A11 and SLC3A2, which are anti-transporter of
cystine and glutamate and are responsible for trans-
porting extracellular cystine into the cell and reducing
it to cysteine. Cystine can be synthesized de novo from
methionine through the sulfur transfer pathway [67],
or imported into cells by other transporters such as
SLC1A1 as substitutes [68]. Cysteine, glutamic acid and
glycine were used as substrates to synthesize glutathione.
HCP1
Fe3+
Fe2+
Fe2+
DcytbSTEAP2 DMT1
Fe3+ Fe2+
Fe3+
ferroheme
ferroheme
HO-1
Fe2+ FPN1
Fe2+
Fe3+
Fe2+
ascorbic acid / low
PH in thestomach
TF
TF
F3+
Fe3+ Fe3+
TF
Glutamate
ROS
Fe2+
Fenton Reaction
lipidperoxidation
PUFA
PUFA-COA
PUFA-PE
LACS4
LPLAT5
LOXs
NRF2
System XC-
Cystine
Glutathione
Synthesis
GCS/GSS
GSH
GSSG
GPX4
GPX4
lipidperoxidation
Fe2+
Ferroptosis
Keap1
STAT3
Fe2+
Fe2+
FPN
TF
TFR1
F3+
LIP
F3+
FSP1
CoQ10
CoQ10H2
Fig. 1 Dietary iron is absorbed by the gastrointestinal tract [55–57], metabolized by the liver into the circulatory system, and distributed
to cardiomyocytes on demand [61]. Ferroptosis is closely related to iron metabolism, amino acid metabolism, lipid metabolism and other metabolic
pathways
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 5 of 16
Yanetal. Diabetology & Metabolic Syndrome (2023) 15:161
Because of its limited concentration in cells, cysteine is
considered a key rate-limiting step in the synthesis of
GSH.
GPX4 is the main scrubber of lipid peroxides in cells,
which can directly reduce lipid peroxides in membranes
to non-toxic lipid alcohols. e esterification of oxi-
dized fatty acids and cholesterol hydroperoxides can
only be reduced by GPX4, a member of the GPX fam-
ily of enzymes [69]. Selenium is an essential component
of selenium-containing cysteine proteins (including
but not limited to GPX4), which can boost cell antioxi-
dant capacity during ferritic damage and is required for
GPX4’s REDOX enzyme function [70, 71]. Selenocysteine
can not only reduce selenol (SeH) but also oxidize selenic
acid (SeOH) in the reduction process of lipid hydroper-
oxide catalyzed by GPX4. is dynamic process includes:
(1) the selenoalcohol form of selenocysteine (GPX4-SeH)
is converted to selenoacid intermediate (GPX4-SeOH)
by hydrogen peroxide, and hydrogen peroxide (LOOH)
is reduced to alcohol (LOH); (2) e intermediate reacts
with glutathione to form water and selenium-glutathione
admixture (GPX4-Se-SG); (3) Systemic XC-mediated
cystine absorption, followed by GSH synthesis and GPX4
activation, is critical in protecting cells from iron sagging.
erefore, a deficiency of selenium in serum or cyto-
plasm is likely to impair GPX4 function and ultimately
lead to the accumulation of lipid peroxides, leading to
iron sagging [72]. Studies have revealed that GSH is a
crucial cofactor for GPX4 and that its availability controls
its capacity to operate normally. e XC system, which
is widely distributed in the phospholipid bilayer, controls
GPX4 activity, that’s dependent on the exchange of extra-
cellular cystine and intracellular glutamate.
Recently, it was discovered that FSP1 works indepen-
dently of glutathione to stop harmful peroxidation by
rebuilding reduced coenzyme Q10 [69, 73]. CoQ, also
known as ubiquitone, CoQ10 is the most common form
of CoQ used as a dietary supplement. CoQ10 is an endog-
enous inhibitor of iron sagging [74]. By transporting
electrons from complex I and II to complex III, CoQ10
plays a crucial part in the mitochondrial electron trans-
port chain. Additionally, ubiquitin alcohol (CoQ10H2),
the reduced form of CoQ10, is employed as a powerful
lipophilic antioxidant in the recovery of other antioxi-
dants like tocopherol and ascorbate. AIFM2(apoptosis-
inducing factor mitochondrial associated 2)/FSP1 has
been identified as an inhibitor of iron sagging through
CoQ10 production [69, 73], which is parallel to the GSH-
dependent GPX4 pathway.
Other metabolic processes for amino acids involved in
ferroptosis likewise heavily rely on the meglutarate path-
way. It controls the manufacture of selenoproteins and
other antioxidant molecules like ubiquitin more than
any other cellular metabolic process [75]. Isopentenyl
pyrophosphate, a metabolic intermediary of the mevaler-
ate pathway, is necessary for the creation of numerous
compounds, including ubiquitin [76]. Ubiquitin alco-
hol can inhibit lipid peroxidation in plasma membrane
and block iron ptosis. e antagonist of FIN56 is fer-
ropendant inhibitory protein 1 (FSP1, formerly known
as AIFM2), an enzyme that catalyzes the conversion of
ubiquitin-ketone to ubiquitin-alcohol [77]. Although
practically all lipid membranes contain ubiquitin ketone,
only locations outside of the mitochondria are protected
from lipid peroxidation by FSP1 dependent ubiquitin
ketone modification [77]. In addition, the dysfunction
of the xc-system that leads to glutathione depletion also
occurs in ferroptosis [78–80]. Oxidative glutamate intox-
ication, also known as oxidative glutamate intoxication, is
a glutamate-induced cell death mediated by blocking of
the xc-system [81].
Lipid metabolism
e production of lipid peroxides is iron-dependent. A
high iron diet increases their susceptibility to iron pto-
sis by increasing extracellular iron concentration [82,
83]. Heat shock protein B family member 1 (HSPB1)
and other proteins that reduce intracellular iron lev-
els can also affect intracellular iron sensitivity [84]. e
release of iron from ferritin is mostly dependent on fer-
ritin phagocytosis, which is mediated by nuclear receptor
coactivator 4 (NCOA4). When ferritin is phagocytosed,
NCOA4 attaches to it and moves it to the lysosomes for
iron release and destruction [85]. High intracellular iron
concentration may then further induce ferroptosis.
Iron participates in lipid oxidation in the following
three possible ways:(I) Fenton reaction [86], in which Fe2+
acts as a catalyst to supply electrons to O2 or H2O2, pro-
moting the production of ROS and lipid peroxides; (II)
Lipid autooxidation catalyzed by iron-catalyzed enzymes;
(III) Lipid peroxidation catalyzed by iron-containing
LOX [78]. NRF2 plays a key role in mediating glycolipid
toxic-dependent ferric sagging in H9C2 cardiomyocytes
[18]. At the molecular level, glucolipid toxicity is most
likely caused by activation of NRF2-driven ACSL4 tran-
scription and inhibition of FSP1 expression, inhibition
of NRF2-regulated GPX4 transcription and damage of
NRF2-coordinated iron metabolism gene network, thus
leading to iron death of cardiomyocytes and promoting
the progression of DC [18].
In addition to intracellular iron buildup, iron ptosis is
also caused by a disturbance of lipid metabolism. Ara-
chidonic acid and docosahexaenoic acid are two poly-
unsaturated fatty acids (PUFAs) found in phospholipids
like phosphatidylcholine that mediate intracellular signal
transmission and are most vulnerable to oxidation during
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 6 of 16
Yanetal. Diabetology & Metabolic Syndrome (2023) 15:161
ferroptosis [86]. PUFAs will undergo repetitive peroxida-
tion when iron-dependent ROS levels are too high, which
will cause cell membrane malfunction and eventually
lead to iron-dependent cell death [87]. Free PUFAs are
susceptible to lipid peroxidation and substrates for lipid
signal transduction production. ACSL4 [87] and LPCAT3
[88] exerts stringent control over the peroxide substrate
PUFAs at the unsaturated level. e amount of intracel-
lular lipid peroxidation and, consequently, the outcome
of ferroptosis are determined by the abundance and dis-
tribution of PUFA. e three main characteristics of fer-
roptosis and associated indications of diabetes mellitus
and its consequences are the down-regulation of GPX4
expression, clearance of lipid reactive oxygen species, and
rise in mRNA level [89–91].
Some genes that control PUFA production and pre-
serve the integrity of healthy cell membranes may also
have an impact on the emergence of ferroptosis in addi-
tion to lipid peroxidase. e most significant indicator
of ferroptosis is arachidonoyl-(AA-) OOH-phosphati-
dylethanolamine (PE) [92]. e conversion of AA to
AA-COA is driven by the long chain family of acyl-CoA
synthases 4 (ACSL4). ACSL4, a member of the long chain
family of acyl-CoA synthases, is a reliable marker of fer-
roptosis and can induce the production of 5-hydroxyle-
thyldieneacetic acid (5-HETE), the signature signal of
ferroptosis [93]. Unsaturated arachidonic acid is demon-
strated to be inserted into phosphatidylethanolamine in
the phospholipid membrane of cells by lysophosphatidyl
choline acyltransferase 3 (LPCAT3) and ACSL4, later,
AA-coa is converted to AA-PE by esterification pro-
moted by LPCAT3 [87, 93]. In the last step, the formation
of AA-oh-PE requires the oxidation of AA-PE catalyzed
by lipoxyphenase (LOXs) [94]. Ultimately, uncontrolled
accumulation of AA-oh-PE leads to iron sagging and
exacerbates erastin and RSL3-induced ferroptosis in can-
cer cells [94].
The cellular processes offerroptosis inDC
In the early phases of the condition, DC typically causes
cell death, myocardial fibrosis, left ventricular hyper-
tension, unfavorable remodeling, and progression of
diastolic dysfunction [95, 96]. At this stage, if strict meta-
bolic control is applied, DC pathological changes can
be reversed. With the progression of the disease, DC
deforms to systolic dysfunction with reduced ejection
fraction (EF) in the advanced stage, and its myocardial
changes are irreversible, resulting in the final clinical
manifestations of heart failure [97, 98]. Excessive oxida-
tive stress mediated by lipid peroxidation and iron over-
load is one of the important causes of myocardial injury
in DC. Many studies have demonstrated that diabetic
heart disease can be effectively treated by targeting the
source of oxidative stress or endogenous antioxidant
defense systems [99–102], as well as removing ROS [103].
erefore, inhibiting lipid peroxidation caused by fer-
roptosis and iron overload may be of great significance
to enhance the antioxidant capacity of the body and
reduce the pathological damage of DC [100]. is sec-
tion focuses on the role of ferroptosis in DC pathological
changes and related pathways, and Table2 summarizes
the role of iron-related protein in heart metabolism con-
firmed by recent experiments.
Cell death
In the type 1 diabetes and type 2 diabetes models, the
main forms of diabetic heart cell death include apopto-
sis, autophagy and necrosis [112, 113]. Tissue homeo-
stasis requires low apoptosis and autophagy to remove
unwanted cells, organs, and proteins [27, 112]. However,
the increase in apoptosis and the subsequent replace-
ment of fibrosis in the heart is considered a harmful
phenomenon [112]. Recently, Cai team [12] confirmed
the function of ferroptosis in DC and found that sul-
foraphane activated NRF2 to prevent DC by suppressing
ferroptosis, indicating that DC may be treated by doing
so. Because mature mammalian hearts have a limited
ability for myocardial regeneration, preventing myocar-
dial cell death may be a key strategy for treating DC [18].
e destiny of cardiac muscle cells is tightly correlated
with mitochondrial iron content. e energy required
for cardiac physiological activations is provided by iron-
sulfur clusters (ISCs), which are produced when mito-
chondria undergo oxidative phosphorylation [114]. As
reported by Wofford et al., iron deficiency may limit
energy output, while iron overload may produce excess
ROS and lead to mitochondrial destruction [115, 116].
e toxic hydroxyl radicals produced by the reaction of
ROS with mitochondria, in addition to the ROS-related
toxicity in mitochondria, also contribute to the depolari-
zation of mitochondrial membrane potential (MMP) and
the opening of mitochondrial penetration pores, which
results in mitochondrial structural swelling and dysfunc-
tion [117, 118], and initiating the process of apoptosis
and necrosis [119]. At the same time, mitochondrial dys-
function, in turn, leads to mitochondrial iron homeosta-
sis disorders, which further aggravate the ferroptosis.
Mitochondrial iron metabolism is finely regulated by
a variety of proteins. Major sources of iron intake from
the cytoplasm to the mitochondria are the TF-TFR
complex and FT breakdown in lysosomes, which are
controlled by mitoferrin 2 (MFRN) and the mitochon-
drial calcium unit transporter (MCU) [120]. FtMt is a
critical regulator of mitochondrial iron homeostasis,
particularly in cardiomyocytes, and has a highly homol-
ogous sequence to FTH, which has multidirectional
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 7 of 16
Yanetal. Diabetology & Metabolic Syndrome (2023) 15:161
effects on iron input by transferring iron from the
cytoplasm to the mitochondria [121]. rough this
regulatory mechanism, it was found that increased
FtMt expression in the heart muscle is the main cause
of reduced iron content in mitochondrial LIP, leading
to a decrease in systemic ROS production [122]. Stud-
ies have demonstrated that the overexpression of FtMt
can snare iron from the mitochondria and shield cells
against ferroptosis [123]. erefore, it is conceivable
that FtMt could be a potential target for preserving iron
homeostasis in cardiomyocytes. Another study revealed
that by controlling iron metabolism, preserving mito-
chondrial function, and elevating GSH levels, the mito-
chondrial protein iron-sulfur cluster assembase (ISCU)
can lessen the toxicity of DHA [79], which is promising
as a new target to interfere with ferroptosis.
In fact, a vicious loop that traps cardiomyocytes and
worsens ROS-induced damage is created when hypoxic-
inducing factor (HIF) is overactive. HIF upregulates the
transferrin receptor 1 (TFR1) expression on FtMt [124].
High levels of ROS cause direct oxidative damage to pro-
teins, lipids, and DNA, while ROS is an important trig-
ger for inflammation [125–127]. Studies have shown
that inflammation is also one of the pathogenesis of DC
patients [128]. Damage-associated molecular patterns
(DAMPs) are commonly regarded as immunological
mediators for distinct RCD kinds. DAMPs are endog-
enous molecules that can be generated by dying or dying
cells and ultimately induce inflammation and immuno-
logical response by attaching to the receptors of different
immune cells, such as macrophages and monocytes [129].
Recent studies have shown that HMGB1(high mobility
box1) is a typical DAMP released by ferriogenic cells,
Table 2 Iron metabolism disturbances described in heart
Iron metabolism level Protein Experimental procedure Result References
Iron absorption HO‐1 6 months of myricetin treatment (200 mg/
kg/d) in DC mice IκBα/NFκB inhibited and Nrf2/HO-1
enhanced [104]
Cardiac hypertrophy, apoptosis, and intersti-
tial fibrosis improved
Dcytb In MDCK cells expressing an inducible
duodenal cytochrome b-green fluorescent
protein fusion construct
DMT1 and copper transporter 1 help Dcytb
ingest iron and copper [105]
Hephaestatin The whole body and intestine-specific
hephaestin knockout mice Hephaestin is not necessary
because both mouse strains survived [106]
Duodenal enterocytes stored iron in knock-
out mice, reducing intestinal iron absorption
TFR1 Used wild-type and autophagy-deficient
cells, BECN1± and LC3B−/− During ferroptosis, ROS-induced autophagy
controls ferritin degradation and TfR1
expression
[107]
DMT1 Acute myocardial infarction and cardiomyo-
cyte hypoxia mouse models DMT1 knockdown effectively decreased
H/R-induced cardiac cell ferroptosis,
while overexpression increased it
[108]
Iron storage Ferritin Mice lacking ferritin H in cardiomyocytes
were feeded these mice a high-iron diet SLC7A11-mediated ferroptosis causes car-
diomyopathy from cardiac ferritin H loss [109]
Iron transport and utilization FPN1 Sulforaphane-treated STZ-induced diabetic
rats with cardiac IRI models Activation of NRF2/FPN1 pathway attenu-
ates myocardial ischemia–reperfusion injury
in diabetic rats by regulating iron homeosta-
sis and ferroptosis
[65]
Glucose and hypoxia/reoxygenation-
induced cardiomyocytes injury models
treated with erastin in vitro
Frataxin Cardiomyocyte-specific HIF-1α knockout
mice Frataxin, an iron storage protein
under hypoxia, prevented mitochondrial
iron overload and ROS and preserved car-
diomyocyte membrane integrity
[110]
Iron homeostasis regulation Hepcidin Neonatal mice with apical resection-induced
heart regeneration Macrophages lacking hepcidin promoted
cardiomyocyte proliferation [111]
IL-6 increased hepcidin in inflammatory
macrophages
STAT3 Hepcidin deficiency phosphorylated STAT3,
releasing IL-4 and IL-13
HIF Cardiomyocyte-specific HIF-1α knockout
mice HIF-1α-frataxin signaling protects
against hypoxia/ischemia [110]
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 8 of 16
Yanetal. Diabetology & Metabolic Syndrome (2023) 15:161
activated by macrophages and produced proinflamma-
tory cytokines, causing inflammation [130, 131]. In addi-
tion, intermediates or end products of lipid peroxidation
may be other sources of modulating immune responses
during cell death caused by iron overdose [132]. Due to
the minimal immune inflammatory response associated
with ferrotosis, specific immunological signals associated
with the early or late stages of ferrotosis remain unclear.
Autophagy
Under normal physiological conditions, the heart’s glu-
cose metabolism is mainly glucose formation, the path-
way to pentaphosphate, and the production of glucose.
Diabetes alters myocardial substrate utilization [1, 112],
resulting in decreased glucose oxidation, increased fatty
acid oxidation, and decreased glycolysis. AGE forma-
tion and unadapted hexosamine biosynthesis pathways
(HBPs) also contribute to glycotoxicity [112, 133]. Dia-
betes-related cardiac lipotoxicity is not unique to type 2
diabetes hearts, but can also be observed in type 1 diabe-
tes [134, 135]. e utilization of this alteration is due in
part to the increased expression of myofilm transporters
(especially CD36) on cardiomyocytes that mediate the
uptake of free fatty acids to the heart, and the decreased
expression and myofilm localization of glucose transport-
ers (i.e. GLUT4) on the heart [112, 134, 136], resulting
in increased myocardial lipid content [134, 137]. Both
lipotoxicity and glycolipid toxicity can induce autophagy
inhibition, and glycolipid toxicity is the most effective
inducer of myocardial autophagy inhibition [18]. Because
myocardial lipid deposits are associated with high lipid
content, diabetes type 1 exacerbates over time [135], it
is speculated that chronic glucolipid toxicity induces
inhibition of myocardial autophagy in type 1 diabetes.
Autophagic defects stop the defense through NRF2, initi-
ate the pathological process of cardiovascular ferroptosis
through NRF2, and aggravate DC progression [18]. is
suggests that the basic mechanism of DC’s ferroptosis
can be linked to NRF2.
NRF2-mediated iron sagging in cardiomyocytes may be
downstream of myocardial autophagy inhibition, result-
ing in the progression of type 1 diabetes cardiomyopa-
thy over time, according to H9C2 cells with impaired
autophagy that replicate the cardiac autophagy inhibition
phenotype in chronic type 1 diabetes [18]. e unique
function of NRF2 in regulating the fate of cardiomyocytes
by balancing the expression of genes with opposing roles
in cell death is further highlighted by these findings. e
underlying dysregulation of NRF2 driver gene expression
in many pathological contexts may be the cause of the
NRF2-mediated dichotomy. ese findings help explain
NRF2-mediated cytotoxicity in cardiomyocytes [138],
which appears to be a potential inducer of ferroptosis
[139].
Ferritin phagocytosis is a mechanism selective
autophagy process [140]. Some studies support the idea
that activation of ferroptosis depends on induction of
autophagy [140–143]. NCOA4 releases more iron from
ferritin [85] through ferritin phagocytosis, resulting in
ferroptosis. In addition, there is evidence that iron droop-
ing is accelerated when cDNA transfection [141] forces
an increase in NCOA4 expression, but is limited when
NCOA4 gene is absent [141]. is suggests that excessive
expression of NCOA4 genes promotes fertin phagocyto-
sis, releases excess iron, and accelerates cardiac damage
through ferroptosis.
Myocardial brosis
e lack of accumulation and structural remodeling of
ECM components in the heart (also called myocardial
fibrosis) leads to abnormal filling of the left ventricle
and diastolic dysfunction [144–146]. Evidence suggests
that iron contributes to the development of myocardial
fibrosis [147], and the significant presence of myocardial
fibrosis is linked to cardiac problems and cardiovascu-
lar risk factors [148]. Iron overload may amplify its toxic
effect on diabetic heart tissue through oxidative stress,
leading to myocardial fibrosis, which is mainly mani-
fested by increased level of type III collagen [149, 150],
and aggravates myocardial dysfunction.
It is believed that oxidative damage contributes to
iron-mediated cardiac fibroblast activation, resulting in
enhanced myocardial fibrosis [148]. An increase in free
radical generation from too much iron results in more
peroxidation and antioxidant usage [151]. Studies have
revealed that oxidative stress affects a pro-fibrosis factor,
and that an increase in ROS can stimulate the release of
collagen [152, 153]. Calcium channel blockers can pre-
vent iron entrance into cardiomyocytes and lower the
volume of collagen in heart tissue since another study
revealed that calcium channels are the primary input
locations for iron in cardiovascular disorders brought on
by iron excess [154–156]. In conclusion, controlling or
suppressing the oxidative stress caused by the overload of
iron can reduce to some extent the heart fibrosis caused
by the overload of iron. At present, the research on the
mechanism of myocardial fibrosis mainly focuses on
oxidative stress, but research into iron overload in heart
failure is very limited and the therapeutic mechanisms of
existing drugs are still unknown.
Microvascular endothelial dysfunction
In the autopsy myocardial samples of diabetic patients,
capillaries and arteries decreased and the thickness of the
walls of the arteries increased [157]. Both type 1 diabetes
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 9 of 16
Yanetal. Diabetology & Metabolic Syndrome (2023) 15:161
and type 2 diabetes patients showed increased coronary
resistance and decreased coronary reserve [158], as well
as decreased myocardial blood volume and flow [159].
ese diabetes-induced microvascular damage reduces
the oxygen and other nutrients that are supplied to the
heart muscle. ese microvascular injuries can further
aggravate the impairment of the function of the coronary
endothelial cells and the increase in the hardness of the
microvascular cells due to persistent diabetes [160–162].
One of the primary target tissues for iron overload injury,
which is thought to be caused by an excess of ROS, is vas-
cular endothelial cells (VECs) [163, 164].
In most diabetic patients, serum ferritin levels are high,
and ferritin can cause complications in diabetic blood
vessels due to iron-induced oxidation stress. High levels
of ferritin in type 2 diabetes are closely linked to compli-
cations of diabetes vascularity through interactions with
VEGF [165]. Endothelial dysfunction is often associated
with alterations in the ROS/asymmetric dimethylargi-
nine (ADMA)/eNOS/dimethylarginine dimethylamino-
hydrolase II (DDAHII) pathway [166]. Too much free
iron causes the cytoplasm to overflow with ROS. As a
result, excessive ROS activates two vicious cycles—one
involving the ADMA/eNOS/DDAHII/NO route and the
other involving the ROS-induced ROS release (RIRR)
mechanism [167]. e former exerts biological effects
in two ways: excessive ROS inhibits DDAHII and accu-
mulates ADMA [167]; ADMA not only competitively
inhibits eNOS activity and reduces NO synthesis, but
also induces uncoupling of eNOS to produce more
ROS, thus making ROS cycle back and back, forming a
vicious cycle. e latter, excess ROS enters mitochondria,
thereby weakening MMP, opening mPTP, and activating
the RIRR mechanism [167, 168], creating another vicious
cycle. Together, these two cycles induce a burst of ROS
that leads to mitochondrial dysfunction, which in turn
damages VECs. erefore, interrupting any of the steps
in the above cycle can end the associated vicious cycle
and prevent the onset and progression of injury. For
example, quercetin can increase the expression and activ-
ity of DDAII through ROS/ADMA/DDAII/eNOS/NO
pathway, decrease ADMA level, increase NO content,
increase p-eNOS/eNOS ratio, and reduce the oxidative
stress and mitochondrial dysfunction induced by iron
overload [169].
In addition, recent studies have shown that perox-
iredoxin-2 (PRDX2) may play an important pivotal role
in ferroptosis-mediated cardiac microvascular injury.
PRDX2 is a redox-sensitive thiol-specific peroxidase
that protects cells from oxidative stress and is highly
expressed in vascular endothelial cells [170]. According
to the results of Chen etal. [163], PRDX2 expression is
decreased in cardiac microvascular endothelial cells,
and endothelium-specific overexpression of PRDX2 can
improve mitochondrial function, restore GPX4 expres-
sion, reduce Fe2+ load and reduce lipid peroxidation
accumulation in cardiac microvascular endothelial cells.
PRDX2 was identified as a downstream target of Isohes-
peretin (ISO). ISO, an analogue of resveratrol, can inhibit
mitochondrial translocation and mitochondria-related
ferroptosis through the PRDX2-MFN2-ACSL4 path-
way, and improve the density and perfusion of cardiac
microvessels in diabetic patients [163]. ese findings
open an important new arena for the mechanistic study
of the pathogenesis of diabetic cardiomyopathy.
Ferroptosis inDC‑associated cardiomyopathy
In their thorough overview and analysis of the role of fer-
roptosis in cardiomyopathy, Li et al. [171], underlined
that iron fall may one day be used as a treatment for car-
diomyopathy. We found that ferroptosis still has many
unexplored areas in DC and related cardiomyopathy.
Doxorubicin induces the onset of cardiomyopathy
by inserting into mitochondrial DNA and disrupting
5′-aminolevulinic acid synthetase 1-dependent heme
synthesis, causing iron ptosis and cardiotoxicity [172].
HCBP6, also known as FUN14 containing domain 2, is
a highly conserved and widely expressed mitochondrial
outer membrane protein that interacts with the mito-
chondrial glutathione transporter SLC25A11 to control
mitoGSH, which in turn controls iron stress [173]. How-
ever, it is still unclear how mitochondria detect stress to
initiate ferroptosis under pathological circumstances.
In a recent study, Ferroptosis in hypertensive car-
diomyopathy and DC shared 32 differentially expressed
genes—26 up-regulated and 6 down-regulated—and
three hub genes—periostin, insulin-like growth factor
binding protein-5, and fibromodulin [174]. Ferropto-
sis in DC and hypertension cardiomyopathy is linked to
STAT3, lysophosphatidylcholine acyltransferase 3, and
solute carrier family 1 member 5. ree hub genes may
be cardiomyopathy biomarkers or therapeutic targets
[174]. Another bioinformatics analysis found 15 ferrop-
tosis-related genes (4 up-regulated and 11 down-regu-
lated) in ischemic cardiomyopathy and 17 in idiopathic.
ese genes are mostly engaged in the MAPK signaling
pathway in ischemic cardiomyopathy and the PI3K-Akt
pathway in idiopathic cardiomyopathy [175]. Future bio-
markers for cardiomyopathy prognosis and treatment
may include these hub genes and medicines.
Targeted interventions andprospects
Ferroptosis is mainly characterized by iron overload,
lipid peroxidation and the imbalance of antioxidant sys-
tem. erefore, in view of the above characteristics, we
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 10 of 16
Yanetal. Diabetology & Metabolic Syndrome (2023) 15:161
can consider the following three aspects to inhibit ferrop-
tosis: first, reduce the content of iron in the body, such
as dietary restriction of iron intake, promote the utiliza-
tion of iron ion or accelerate the removal of iron ion; sec-
ond, lipotoxicity reduction; last, improve the antioxidant
capacity, such as the use of antioxidants.
Drugs ortherapies targeting forexcess iron
Deferoxamine (DFO), deferasrorox, and deferiprone are
FDA-approved cardiac iron chelators, of which DFO
decreases mouse heart cell mitochondrial ROS and
enhances endothelium-dependent vasodilation in coro-
nary disease patients [176, 177]. Deferasrox is an oral
iron chelating agent that protects heart tissue by reducing
iron concentration [178, 179]. EDTA(ethylenediamine
tetraacetic acid) can alleviate adverse cardiovascular out-
comes in patients with acute myocardial infarction [180,
181]. Unfortunately, chelation is complex and has multi-
ple serious adverse effects, such as auditory toxicity, oste-
otoxicity, and growth retardation [182].
Anti-ferroptosis drugs are considered as a new strat-
egy for the treatment of myocardial injury. Ferrosta-
tin-1, a ferroptosis inhibitor, can alleviate the structural
and functional disorders of cardiomyocytes mediated
by the loss or low expression of the ferroptosis inhibitor
XCT, and reduce the levels of Ang II-induced ferropto-
sis biomarkers Ptgs2, malondialdehyde and reactive oxy-
gen species [183]. e newly developed polydopamine
nanoparticles, as a novel iron ptosis inhibitor, effec-
tively reduced Fe2+ deposition and lipid peroxidation in
a mouse model of myocardial I/R injury [184] and have
interesting properties in restoring mitochondrial func-
tion in h9c2 cells. Although this novel technique is still
in its infancy, it has great potential for the treatment of
cardiac injury caused by ferroptosis.
Canagliflozin, a SGLT2i, can effectively protect the
heart in a variety of myocardial injury diseases, such as
autoimmune myocarditis [185] and myocardial lipid
toxicity [186]. To prevent DC ferroptosis in DC mice
and cells, canagliflozin can up-regulate XCT expression,
down-regulate ferritin heavy chain expression, and acti-
vate the system Xc-/GSH/GPX4 axis [187]. In addition,
canagliflozin may significantly inhibit the expression of
cyclooxygenase-2 and iNOS by activating AMPK path-
way, or inhibit the inflammatory response by reducing
the levels of IL-1, IL-6, TNF-α and other inflammatory
factors in myocardial cells [188], thereby reducing lipo-
toxicity and indirectly inhibiting ferroptosis [189]. ese
studies provide clues for canagliflozin to regulate ferrop-
tosis as an intervention target.
Drugs ortherapies targeting forlipid peroxidation
e introduction of medications to stop the oxidation
process is the treatment for ferroptosis, which is brought
on by the oxidation of phospholipids. Lipvastatin-1 is a
lipophilic RTA (free radical trapping antioxidant) that
maintains the DC endothelium cells’ ability to function
by limiting the spread of free radicals that would other-
wise oxidize lipids [190]. ese drugs are very effective in
the ferroptosis model [191].
However, not all lipid-lowering drugs can reduce iron
death by inhibiting lipid peroxidation, such as statins.
Fluvastatin, lovastatin, and simvastatin belong to a class
of medications called statins that lower blood cholesterol
levels by blocking the enzyme HMGCR, which controls
cholesterol synthesis in the MVA route. By decreas-
ing the formation of isopentane pyrophosphate in the
valvalic acid pathway and limiting the manufacture of
selenoproteins (including GPX4) and coenzyme Q10,
statins encourage mesenchymal cell iron sags or specifi-
cally cause cell death. erefore, statins may aggravate
ferroptosis.
e largest cost on health is posed by the negative
consequences of statin-related muscular symptoms
(SAMS) [192]. Myocardium is a special striated muscle,
and previous reports have shown that the mechanism
of myocardial SAMS mainly focuses on mitochondrial
dysfunction and apoptosis [193, 194]. For the first time,
recent research has demonstrated that atorvastatin pro-
duces ferroptosis by blocking the NRF2-XCT/GPX4
pathway of the intracellular antioxidant system, which
results in fatal lipid peroxidation in myocytes [195].
In vitro experimental studies, a large amount of Fe2+
accumulation, lipid peroxidation and ROS caused by free
iron overload induced by atorvastatin through ferroptosis
triggered by Fenton reaction in muscle cells, and partici-
pated in the process of mitochondrial dysfunction [195].
erefore, the limitations of statins in clinical application
should be fully considered.
In addition, Angiotensin-converting enzyme 2 (ACE2)
has been shown to contribute to the reduction of DCM
and is a substrate for disintegrin and metalloproteinase
protein 17 (ADAM17) [196]. Recent studies have found
that the protein expression and activity of ADAM17 are
up-regulated in the myocardium of diabetic mice, while
the protein expression of ACE2 is down-regulated [24].
e specific knockout of ADAM17 in cardiomyocytes
can reduce cardiac fibrosis and cardiomyocyte apopto-
sis, and improve cardiac dysfunction in DC mice, which
may be related to the activation of AMPK pathway, the
increase of autophagosome formation and the improve-
ment of autophagic flux [24], and indirectly regulate the
process of lipid metabolism. ese results suggest that
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 11 of 16
Yanetal. Diabetology & Metabolic Syndrome (2023) 15:161
ADAM17 inhibition may provide another promising
approach for the treatment of DC.
Targeted enhancement ofantioxidant
NRF2 is recognized as an important antioxidant defence
regulator and is developed as a promising target drug for
DC treatment [197]. In recent years, the two most prom-
ising approaches to limiting the damage of the oxidative
heart caused by diabetes are to inhibit NADPH oxidation
by pharmaceutical activation of NRF2 [126, 198, 199]
and combined NOX1/NOX4 inhibitor GKT137831, as
demonstrated in several preclinical models of diabetes
[200–202].
e current research on NRF2 in the treatment of
ferroptosis is mainly focused on myocardial ischemia–
reperfusion, and there is a lack of research on DC. Dex-
medetomidine can inhibit ferroptosis through AMPK/
GSK-3β/NRF2 axis [203], or by regulating the expression
of ferroptosis-related proteins [204], including SLC7A11,
GPX4, ferritin heavy chain and cyclooxygenase-2, and
activating SLC7A11/GPX4 axis. Reduce myocardial
ischemia–reperfusion injury in rats.
In addition, many traditional Chinese medicine mon-
omers and preparations have shown good effects on
inhibiting ferroptosis by targeting NRF2-related path-
way. Berberine hydrochloride increased cell viability
and MMP by inhibiting NRF2 [205] or by reducing ROS
generation and lipid peroxidation [206], showing a good
inhibitory effect on ferroptosis. Britanin can alleviate
ferroptosis by activating AMPK/GSK3β/NRF2 signal-
ing pathway and up-regulating GPX4 [207]. Naringenin
[23] and Shenmai injection [208] can inhibit iron ptosis
by regulating NRF2/System XC-/GPX4 axis. 6-Gingerol
[209] and curcumin [210] can alleviate myocardial injury
in DC mice and cell models and activate the NRF2/HO-1
pathway by enhancing GPX4 expression. In addition,
6-Gingerol can also reduce the secretion of inflamma-
tory factors IL-1β, IL-6 and TNF-α [209] to alleviate the
inflammatory response.
However, there is considerable controversy in the cur-
rent literature on the role and complications of NRF2 in
diabetes. For example, global low phenotypic knockout of
the endogenous inhibitor of NRF2, Kelch-like ECH-asso-
ciated protein 1 (Keap1), activates the NRF2 gene and
thus inhibits the development of diabetes in db/db mice
[211]. However, paradoxically, it increased insulin resist-
ance and glucose intolerance in mice [212]. e exact
reason for these differences is unknown. Clinical trials
on various stages of NRF2 activators in the treatment of
other diseases are still being conducted [213].
e development of drugs that target the gut micro-
biota and targeted therapy, in addition to NRF2 and
related pathways, has opened up a new realm for the
treatment of ferroptosis. Salidroside is the main compo-
nent of traditional Chinese medicine Rhodiola. Salidro-
side can increase the proportion of probiotics and reduce
the proportion of lactic acid bacteria [214], among which
iron metabolism is related to the abundance of lactic acid
bacteria, thereby reshaping the intestinal flora and lim-
iting the accumulation of iron. Additionally, by activat-
ing the AMPK-dependent signaling pathway, salidroside
can restore mitochondrial membrane potential, improve
mitochondrial biogenesis, enhance mitochondrial iron-
sulfur clusters, restore mitochondrial OXPHOS com-
plex, inhibit DOX-induced mitochondrial ROS, Fe2+, and
lipid peroxidation, and restore mitochondrial ROS and
Fe2+, these effects enhance mitochondrial function while
defending cardiomyocytes [215].
Recent research has shown that 2-vinyl-10H-pheno-
thiazine derivatives, which play the role of ROS scaven-
gers and can treat DOX-induced cardiomyopathy, can be
employed as a family of ferroptosis inhibitors with lim-
ited human Ether-a-go-go associated gene activity [216].
While, it shows good pharmacokinetic properties and
no obvious toxicity invitro and invivo, which provides a
promising lead compound for the development of drugs
targeting ferroptosis.
Conclusions
Different from other types of cell death, ferroptosis is
a new type of cell death that depends on iron overload
and lipid peroxidation. Increasing evidence suggests
that ferroptosis is widely involved in the occurrence and
development of DC. Cardiomyocytes and microvascular
endothelial cells are the main sites of ferroptosis in DC,
involving multiple different pathological pathways such
as mitochondrial dysfunction, oxidative stress, immune
inflammatory response and so on. Among them, oxida-
tive stress runs through the whole process of the disease.
Improving lipid metabolism, improving antioxidant
capacity and promoting iron metabolism are essential
for the treatment of DC. According to existing studies,
ferroptosis and disease progression can be effectively
inhibited by reducing excess iron, enhancing the antioxi-
dant capacity of the body and inhibiting inflammation.
For example, iron inhibitors, iron chelators, some lipid-
lowering drugs and antioxidant drugs have shown good
effects on inhibiting ferroptosis and protecting cardio-
myocytes invitro and invivo. Bioinformatics has shown
unique advantages in screening key genes and core pro-
teins, which provides guidance for targeted intervention.
Meanwhile, the application of some emerging technolo-
gies has also created a precedent for the removal of exces-
sive ROS. e development of nanoparticle technology
provides a new prospect for exploring new drug carriers.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 12 of 16
Yanetal. Diabetology & Metabolic Syndrome (2023) 15:161
ese will prompt us to search for new alternative drugs
or new drug carrier technologies.
Currently, ferroptosis research in cardiovascular dis-
eases is limited and focuses mainly on animal and invitro
experiments. ere are not enough clinical trials and
observations on human cardiovascular diseases. ere-
fore, the specific pathogenic pathways and mechanisms
of ferroptosis in the huge and complex regulatory system
of human body remain unclear. However, it is undeni-
able that the animal and cell experiments of ferroptosis in
DC have laid a solid foundation for the study of DC and
its related cardiomyopathy, connecting the treatment of
cancer and cardiovascular diseases through the applica-
tion of iron chelators, which opens up a new perspective
for the mechanism research of DC and the joint research
of different disciplines.
Acknowledgements
We thank G.J. Jiang for the guidance and revision of this manuscript.
Author contributions
XHY wrote the main text. YX, HBL, MH and ZY retrieve and organize the docu-
ments. GJJ and DQA had great contribution in second time revision, polishing
manuscript, and helping in revising figures.
Funding
This work is funded by grants from the National Natural Science Foundation
of China (Project No. 82260931) and Xinjiang Major Science and Technology
Projects (No. 2A03019).
Availability of data and materials
Not applicable.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
All authors agreed to publish the review.
Competing interests
We declare that we have no competing interests.
Received: 11 April 2023 Accepted: 9 July 2023
Reference:s
1. Jia G, Hill MA, Sowers JR. Diabetic cardiomyopathy: an update of mech-
anisms contributing to this clinical entity. Circ Res. 2018;122(4):624–38.
2. Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation.
2007;115(25):3213–23.
3. Kozakova M, et al. Impact of glycemic control on aortic stiffness, left
ventricular mass and diastolic longitudinal function in type 2 diabetes
mellitus. Cardiovasc Diabetol. 2017;16(1):78.
4. Bjornstad P, et al. Youth with type 1 diabetes have worse strain and
less pronounced sex differences in early echocardiographic markers of
diabetic cardiomyopathy compared to their normoglycemic peers: a
RESistance to InSulin in Type 1 ANd Type 2 diabetes (RESISTANT) Study.
J Diabetes Complicat. 2016;30(6):1103–10.
5. Miao W, et al. Nr2f2 overexpression aggravates ferropto-
sis and mitochondrial dysfunction by regulating the PGC-1α
signaling in diabetes-induced heart failure mice. Mediators Inflamm.
2022;2022:8373389.
6. Qiu J, et al. NADPH oxidase mediates oxidative stress and ventricular
remodeling through SIRT3/FOXO3a pathway in diabetic mice. Antioxi-
dants (Basel). 2022;11(9):1745.
7. Dhalla, N.S., A.K. Shah, and P.S. Tappia, Role of Oxidative Stress in Metabolic
and Subcellular Abnormalities in Diabetic Cardiomyopathy. Int J Mol Sci,
2020. 21(7).
8. Kawata T, et al. Coronary microvascular function is independently
associated with left ventricular filling pressure in patients with type 2
diabetes mellitus. Cardiovasc Diabetol. 2015;14:98.
9. Iwakura K. Heart failure in patients with type 2 diabetes mellitus:
assessment with echocardiography and effects of antihyperglycemic
treatments. J Echocardiogr. 2019;17(4):177–86.
10. Teo YH, et al. Effects of sodium/glucose cotransporter 2 (SGLT2) inhibi-
tors on cardiovascular and metabolic outcomes in patients without dia-
betes mellitus: a systematic review and meta-analysis of randomized-
controlled trials. J Am Heart Assoc. 2021;10(5): e019463.
11. El-Shafey M, et al. Role of dapagliflozin and liraglutide on diabetes-
induced cardiomyopathy in rats: implication of oxidative stress, inflam-
mation, and apoptosis. Front Endocrinol (Lausanne). 2022;13: 862394.
12. Wang X, et al. Ferroptosis is essential for diabetic cardiomyopathy and
is prevented by sulforaphane via AMPK/NRF2 pathways. Acta Pharm Sin
B. 2022;12(2):708–22.
13. Swaminathan S, et al. The role of iron in diabetes and its complications.
Diabetes Care. 2007;30(7):1926–33.
14. Liu Q, et al. Role of iron deficiency and overload in the patho-
genesis of diabetes and diabetic complications. Curr Med Chem.
2009;16(1):113–29.
15. White DL, Collinson A. Red meat, dietary heme iron, and risk of type 2
diabetes: the involvement of advanced lipoxidation endproducts. Adv
Nutr. 2013;4(4):403–11.
16. Dixon SJ, et al. Ferroptosis: an iron-dependent form of nonapoptotic
cell death. Cell. 2012;149(5):1060–72.
17. Stockwell BR, et al. Ferroptosis: a regulated cell death nexus linking
metabolism, redox biology, and disease. Cell. 2017;171(2):273–85.
18. Zang H, et al. Autophagy inhibition enables Nrf2 to exaggerate
the progression of diabetic cardiomyopathy in mice. Diabetes.
2020;69(12):2720–34.
19. Kuethe F, et al. Apoptosis in patients with dilated cardiomyopathy
and diabetes: a feature of diabetic cardiomyopathy? Horm Metab Res.
2007;39(9):672–6.
20. Joubert M, et al. Diabetes-related cardiomyopathy: the sweet story of
glucose overload from epidemiology to cellular pathways. Diabetes
Metab. 2019;45(3):238–47.
21. Wei J, et al. Preliminary evidence for the presence of multiple
forms of cell death in diabetes cardiomyopathy. Acta Pharm Sin B.
2022;12(1):1–17.
22. Wang N, et al. HSF1 functions as a key defender against palmitic
acid-induced ferroptosis in cardiomyocytes. J Mol Cell Cardiol.
2021;150:65–76.
23. Xu S, et al. Naringenin alleviates myocardial ischemia/reperfusion injury
by regulating the nuclear factor-erythroid factor 2-related factor 2
(Nrf2) /System xc-/glutathione peroxidase 4 (GPX4) axis to inhibit fer-
roptosis. Bioengineered. 2021;12(2):10924–34.
24. Xue F, et al. Cardiomyocyte-specific knockout of ADAM17 ameliorates
left ventricular remodeling and function in diabetic cardiomyopathy of
mice. Signal Transduct Target Ther. 2022;7(1):259.
25. Zheng Y, et al. The role of zinc, copper and iron in the pathogenesis of
diabetes and diabetic complications: therapeutic effects by chelators.
Hemoglobin. 2008;32(1–2):135–45.
26. Zou C, et al. Deferiprone attenuates inflammation and myocardial fibro-
sis in diabetic cardiomyopathy rats. Biochem Biophys Res Commun.
2017;486(4):930–6.
27. Levine B, Kroemer G. Biological functions of autophagy genes: a disease
perspective. Cell. 2019;176(1–2):11–42.
28. Dikic I, Elazar Z. Mechanism and medical implications of mammalian
autophagy. Nat Rev Mol Cell Biol. 2018;19(6):349–64.
29. Xu X, Lai Y, Hua ZC. Apoptosis and apoptotic body: disease message
and therapeutic target potentials. Biosci Rep. 2019;39(1):BSR20180992.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 13 of 16
Yanetal. Diabetology & Metabolic Syndrome (2023) 15:161
30. Li X, et al. Advances in the therapeutic effects of apoptotic bodies on
systemic diseases. Int J Mol Sci. 2022;23(15):8202.
31. Galluzzi L, et al. Necroptosis: mechanisms and relevance to disease.
Annu Rev Pathol. 2017;12:103–30.
32. Stockwell BR. Ferroptosis turns 10: Emerging mechanisms, physiological
functions, and therapeutic applications. Cell. 2022;185(14):2401–21.
33. Teng T, et al. Mapping current research and identifying hotspots
of ferroptosis in cardiovascular diseases. Front Cardiovasc Med.
2022;9:1046377.
34. Tsvetkov P, et al. Copper induces cell death by targeting lipoylated TCA
cycle proteins. Science. 2022;375(6586):1254–61.
35. Kahlson MA, Dixon SJ. Copper-induced cell death. Science.
2022;375(6586):1231–2.
36. Bandmann O, Weiss KH, Kaler SG. Wilson’s disease and other neurologi-
cal copper disorders. Lancet Neurol. 2015;14(1):103–13.
37. Luo B, et al. NLRP3 inflammasome as a molecular marker in diabetic
cardiomyopathy. Front Physiol. 2017;8:519.
38. Song Z, Gong Q, Guo J. Pyroptosis: mechanisms and links with fibrosis.
Cells. 2021;10(12):3509.
39. Wang Y, Li Y, Xu Y. Pyroptosis in kidney disease. J Mol Biol. 2022;434(4):
167290.
40. Zeng X, et al. Pyroptosis in NLRP3 inflammasome-related atherosclero-
sis. Cell Stress. 2022;6(10):79–88.
41. Zhang J, Chen X. p53 tumor suppressor and iron homeostasis. FEBS J.
2019;286(4):620–9.
42. Yien YY, et al. FAM210B is an er ythropoietin target and regulates
erythroid heme synthesis by controlling mitochondrial iron import and
ferrochelatase activity. J Biol Chem. 2018;293(51):19797–811.
43. Silva I, et al. Hypoxia enhances H(2)O(2)-mediated upregulation of
hepcidin: Evidence for NOX4-mediated iron regulation. Redox Biol.
2018;16:1–10.
44. Stehling O, Sheftel AD, Lill R. Chapter 12 Controlled expression of iron-
sulfur cluster assembly components for respiratory chain complexes in
mammalian cells. Methods Enzymol. 2009;456:209–31.
45. Yiannikourides A, Latunde-Dada GO. A short review of iron metabolism
and pathophysiology of iron disorders. Medicines (Basel). 2019;6(3):85.
46. Laftah AH, et al. Haem and folate transport by proton-coupled
folate transporter/haem carrier protein 1 (SLC46A1). Br J Nutr.
2009;101(8):1150–6.
47. San Martin CD, et al. Caco-2 intestinal epithelial cells absorb
soybean ferritin by mu2 (AP2)-dependent endocytosis. J Nutr.
2008;138(4):659–66.
48. Gulec S, Anderson GJ, Collins JF. Mechanistic and regulatory aspects
of intestinal iron absorption. Am J Physiol Gastrointest Liver Physiol.
2014;307(4):G397-409.
49. Silva B, Faution P. An overview of molecular basis of iron metabolism
regulation and the associated pathologies. Biochim Biophys Acta.
2015;1852(7):1347–59.
50. Bogdan AR, et al. Regulators of iron homeostasis: new players in metab-
olism, cell death, and disease. Trends Biochem Sci. 2016;41(3):274–86.
51. Soares M, Bach FH. Heme oxygenase-1: from biology to therapeutic
potential. Trends Mol Med. 2009;15(2):50–8.
52. Araujo JA, Zhang M, Yin F. Heme oxygenase-1, oxidation, inflammation,
and atherosclerosis. Front Pharmacol. 2012;3:119.
53. Drakesmith H, Nemeth E, Ganz T. Ironing out Ferroportin. Cell Metab.
2015;22(5):777–87.
54. Hower V, et al. A general map of iron metabolism and tissue-specific
subnetworks. Mol Biosyst. 2009;5(5):422–43.
55. Moi P, et al. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic
leucine zipper transcriptional activator that binds to the tandem NF-E2/
AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci
USA. 1994;91(21):9926–30.
56. Chen Q, et al. LncRNAs regulate ferroptosis to affect diabetes and its
complications. Front Physiol. 2022;13: 993904.
57. Harada N, et al. Nrf2 regulates ferroportin 1-mediated iron efflux and
counteracts lipopolysaccharide-induced ferroportin 1 mRNA suppres-
sion in macrophages. Arch Biochem Biophys. 2011;508(1):101–9.
58. Sui X, et al. RSL3 drives ferroptosis through GPX4 inactivation and ROS
production in colorectal cancer. Front Pharmacol. 2018;9:1371.
59. Dodson M, Castro-Portuguez R, Zhang DD. NRF2 plays a critical role
in mitigating lipid peroxidation and ferroptosis. Redox Biol. 2019;23:
101107.
60. Haddad S, et al. Iron-regulatory proteins secure iron availability in
cardiomyocytes to prevent heart failure. Eur Heart J. 2017;38(5):362–72.
61. Xie Y, et al. Ferroptosis: process and function. Cell Death Differ.
2016;23(3):369–79.
62. Liu Z, et al. Nrf2 knockout dysregulates iron metabolism and increases
the hemolysis through ROS in aging mice. Life Sci. 2020;255: 117838.
63. Lakhal-Littleton S, et al. Cardiac ferroportin regulates cellular iron
homeostasis and is important for cardiac function. Proc Natl Acad Sci
USA. 2015;112(10):3164–9.
64. Yang S, et al. Salmonella effector SpvB interferes with intracellular
iron homeostasis via regulation of transcription factor NRF2. FASEB J.
2019;33(12):13450–64.
65. Tian H, et al. Activation of NRF2/FPN1 pathway attenuates myocardial
ischemia-reperfusion injury in diabetic rats by regulating iron homeo-
stasis and ferroptosis. Cell Stress Chaperones. 2021;27(2):149–64.
66. Lakhal-Littleton S, et al. An essential cell-autonomous role for hepcidin
in cardiac iron homeostasis. Elife. 2016;5:e19804.
67. Hayano M, et al. Loss of cysteinyl-tRNA synthetase (CARS) induces the
transsulfuration pathway and inhibits ferroptosis induced by cystine
deprivation. Cell Death Differ. 2016;23(2):270–8.
68. Hodgson N, et al. Soluble oligomers of amyloid-β cause changes in
redox state, DNA methylation, and gene transcription by inhibiting
EAAT3 mediated cysteine uptake. J Alzheimers Dis. 2013;36(1):197–209.
69. Doll S, et al. FSP1 is a glutathione-independent ferroptosis suppressor.
Nature. 2019;575(7784):693–8.
70. Rotruck JT, et al. Selenium: biochemical role as a component of glu-
tathione peroxidase. Science. 1973;179(4073):588–90.
71. Flohe L, Günzler WA, Schock HH. Glutathione peroxidase: a selenoen-
zyme. FEBS Lett. 1973;32(1):132–4.
72. Friedmann Angeli J, Conrad AM. Selenium and GPX4, a vital symbiosis.
Free Radic Biol Med. 2018;127:153–9.
73. Bersuker K, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to
inhibit ferroptosis. Nature. 2019;575(7784):688–92.
74. Shimada K, et al. Global survey of cell death mechanisms reveals meta-
bolic regulation of ferroptosis. Nat Chem Biol. 2016;12(7):497–503.
75. Moosmann B, Behl C. Selenoproteins, cholesterol-lowering drugs,
and the consequences: revisiting of the mevalonate pathway. Trends
Cardiovasc Med. 2004;14(7):273–81.
76. Holstein SA, Hohl RJ. Isoprenoids: remarkable diversity of form and
function. Lipids. 2004;39(4):293–309.
77. Stockwell BR. A powerful cell-protection system prevents cell death by
ferroptosis. Nature. 2019;575(7784):597–8.
78. Lei P, Bai T, Sun Y. Mechanisms of ferroptosis and relations with regu-
lated cell death: a review. Front Physiol. 2019;10:139.
79. Du J, et al. DHA inhibits proliferation and induces ferroptosis of leuke-
mia cells through autophagy dependent degradation of ferritin. Free
Radic Biol Med. 2019;131:356–69.
80. Tang H, et al. Dual GSH-exhausting sorafenib loaded manganese-silica
nanodrugs for inducing the ferroptosis of hepatocellular carcinoma
cells. Int J Pharm. 2019;572: 118782.
81. Soria FN, et al. Extrasynaptic glutamate release through cystine/
glutamate antiporter contributes to ischemic damage. J Clin Invest.
2014;124(8):3645–55.
82. Wang H, et al. Characterization of ferroptosis in murine models of
hemochromatosis. Hepatology. 2017;66(2):449–65.
83. Panjrath GS, et al. Potentiation of doxorubicin cardiotoxicity by iron
loading in a rodent model. J Am Coll Cardiol. 2007;49(25):2457–64.
84. Sun X, et al. HSPB1 as a novel regulator of ferroptotic cancer cell death.
Oncogene. 2015;34(45):5617–25.
85. Mancias JD, et al. Quantitative proteomics identifies NCOA4 as the
cargo receptor mediating ferritinophagy. Nature. 2014;509(7498):105–9.
86. Yang WS, et al. Peroxidation of polyunsaturated fatty acids by lipoxyge-
nases drives ferroptosis. Proc Natl Acad Sci USA. 2016;113(34):E4966–75.
87. Doll S, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular
lipid composition. Nat Chem Biol. 2017;13(1):91–8.
88. Dixon SJ, et al. Human haploid cell genetics reveals roles for lipid
metabolism genes in nonapoptotic cell death. ACS Chem Biol.
2015;10(7):1604–9.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 14 of 16
Yanetal. Diabetology & Metabolic Syndrome (2023) 15:161
89. Han D, et al. SIRT3 deficiency is resistant to autophagy-dependent fer-
roptosis by inhibiting the AMPK/mTOR pathway and promoting GPX4
levels. J Cell Physiol. 2020;235(11):8839–51.
90. Ajoolabady A, et al. Ferritinophagy and ferroptosis in the management
of metabolic diseases. Trends Endocrinol Metab. 2021;32(7):444–62.
91. Qi Y, et al. Ferroptosis regulation by nutrient signalling. Nutr Res Rev.
2022;35(2):282–94.
92. Kagan VE, et al. Oxidized arachidonic and adrenic PEs navigate cells to
ferroptosis. Nat Chem Biol. 2017;13(1):81–90.
93. Yuan H, et al. Identification of ACSL4 as a biomarker and contributor of
ferroptosis. Biochem Biophys Res Commun. 2016;478(3):1338–43.
94. Shintoku R, et al. Lipoxygenase-mediated generation of lipid perox-
ides enhances ferroptosis induced by erastin and RSL3. Cancer Sci.
2017;108(11):2187–94.
95. Bildirici U, et al. Diagnostic value of poor R-wave progression in electro-
cardiograms for diabetic cardiomyopathy in type 2 diabetic patients.
Clin Cardiol. 2010;33(9):559–64.
96. Shah AS, et al. A cross sectional study to compare cardiac structure and
diastolic function in adolescents and young adults with youth-onset
type 1 and type 2 diabetes: the SEARCH for Diabetes in Youth Study.
Cardiovasc Diabetol. 2021;20(1):136.
97. Kannel WB, Hjortland M, Castelli W. Role of diabetes in congestive heart
failure: the Framingham study. Am J Cardiol. 1974;34(1):29–34.
98. Maya L, Villarreal FJ. Diagnostic approaches for diabetic cardiomyopathy
and myocardial fibrosis. J Mol Cell Cardiol. 2010;48(3):524–9.
99. Ni R, et al. Therapeutic inhibition of mitochondrial reactive oxygen spe-
cies with mito-TEMPO reduces diabetic cardiomyopathy. Free Radic Biol
Med. 2016;90:12–23.
100. Byrne NJ, et al. Therapeutic potential of targeting oxidative stress in
diabetic cardiomyopathy. Free Radic Biol Med. 2021;169:317–42.
101. Lu S, et al. Hyperglycemia acutely increases cytosolic reactive oxygen
species via O-linked GlcNAcylation and CaMKII activation in mouse
ventricular myocytes. Circ Res. 2020;126(10):e80–96.
102. Tong M, et al. Mitophagy is essential for maintaining cardiac func-
tion during high fat diet-induced diabetic cardiomyopathy. Circ Res.
2019;124(9):1360–71.
103. Nie Z, et al. A Multifunctional integrated metal-free MRI agent for early
diagnosis of oxidative stress in a mouse model of diabetic cardiomyo-
pathy. Adv Sci (Weinh). 2023;10(7): e2206171.
104. Liao HH, et al. Myricetin possesses potential protective effects on
diabetic cardiomyopathy through inhibiting IκBα/NFκB and enhancing
Nrf2/HO-1. Oxid Med Cell Longev. 2017;2017:8370593.
105. Wyman S, et al. Dcytb (Cybrd1) functions as both a ferric and a cupric
reductase in vitro. FEBS Lett. 2008;582(13):1901–6.
106. Fuqua BK, et al. The multicopper ferroxidase hephaestin enhances
intestinal iron absorption in mice. PLoS ONE. 2014;9(6): e98792.
107. Park E, Chung SW. ROS-mediated autophagy increases intracellular iron
levels and ferroptosis by ferritin and transferrin receptor regulation. Cell
Death Dis. 2019;10(11):822.
108. Song Y, et al. Human umbilical cord blood-derived MSCs exosome
attenuate myocardial injury by inhibiting ferroptosis in acute myocar-
dial infarction mice. Cell Biol Toxicol. 2021;37(1):51–64.
109. Fang X, et al. Loss of cardiac ferritin H facilitates cardiomyopathy via
Slc7a11-mediated ferroptosis. Circ Res. 2020;127(4):486–501.
110. Nanayakkara G, et al. Cardioprotective HIF-1α-frataxin signaling
against ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol.
2015;309(5):H867–79.
111. Zlatanova I, et al. Iron regulator hepcidin impairs mac-
rophage-dependent cardiac repair after injury. Circulation.
2019;139(12):1530–47.
112. Bugger H, Abel ED. Molecular mechanisms of diabetic cardiomyopa-
thy. Diabetologia. 2014;57(4):660–71.
113. Spallotta F, et al. Stable oxidative cytosine modifications accumulate
in cardiac mesenchymal cells from type2 diabetes patients: rescue
by α-ketoglutarate and TET-TDG functional reactivation. Circ Res.
2018;122(1):31–46.
114. Paul BT, et al. Mitochondria and iron: current questions. Expert Rev
Hematol. 2017;10(1):65–79.
115. Kruszewski M. Labile iron pool: the main determinant of cellular
response to oxidative stress. Mutat Res. 2003;531(1–2):81–92.
116. Wofford JD, Chakrabarti M, Lindahl PA. Mössbauer spectra of mouse
hearts reveal age-dependent changes in mitochondrial and ferritin
iron levels. J Biol Chem. 2017;292(13):5546–54.
117. Sripetchwandee J, et al. Blockade of mitochondrial calcium uniporter
prevents cardiac mitochondrial dysfunction caused by iron overload.
Acta Physiol (Oxf). 2014;210(2):330–41.
118. Chan S, et al. Deferiprone inhibits iron overload-induced tissue factor
bearing endothelial microparticle generation by inhibition oxidative
stress induced mitochondrial injury, and apoptosis. Toxicol Appl
Pharmacol. 2018;338:148–58.
119. Halestrap AP, et al. Mitochondria and cell death. Biochem Soc Trans.
2000;28(2):170–7.
120. Gordan R, et al. Involvement of cytosolic and mitochondrial
iron in iron overload cardiomyopathy: an update. Heart Fail Rev.
2018;23(5):801–16.
121. Santambrogio P, et al. Mitochondrial ferritin expression in adult mouse
tissues. J Histochem Cytochem. 2007;55(11):1129–37.
122. Campanella A, et al. Mitochondrial ferritin limits oxidative damage
regulating mitochondrial iron availability: hypothesis for a protective
role in Friedreich ataxia. Hum Mol Genet. 2009;18(1):1–11.
123. Maldonado EN, et al. Voltage-dependent anion channels modulate
mitochondrial metabolism in cancer cells: regulation by free tubulin
and erastin. J Biol Chem. 2013;288(17):11920–9.
124. Tang WH, et al. Polyol pathway mediates iron-induced oxida-
tive injury in ischemic-reperfused rat heart. Free Radic Biol Med.
2008;45(5):602–10.
125. Wilson AJ, et al. Reactive oxygen species signalling in the diabetic heart:
emerging prospect for therapeutic targeting. Heart. 2018;104(4):293–9.
126. Sharma A, et al. Oxidative stress and NLRP3-inflammasome activity as
significant drivers of diabetic cardiovascular complications: therapeutic
implications. Front Physiol. 2018;9:114.
127. Hölscher ME, Bode C, Bugger H. Diabetic cardiomyopathy: does the
type of diabetes matter? Int J Mol Sci. 2016;17(12):2136.
128. Dinh W, et al. Elevated plasma levels of TNF-alpha and interleukin-6 in
patients with diastolic dysfunction and glucose metabolism disorders.
Cardiovasc Diabetol. 2009;8:58.
129. Tang D, et al. PAMPs and DAMPs: signal 0s that spur autophagy and
immunity. Immunol Rev. 2012;249(1):158–75.
130. Wen Q, et al. The release and activity of HMGB1 in ferroptosis. Biochem
Biophys Res Commun. 2019;510(2):278–83.
131. Yu Y, et al. The ferroptosis inducer erastin enhances sensitivity of acute
myeloid leukemia cells to chemotherapeutic agents. Mol Cell Oncol.
2015;2(4): e1054549.
132. FriedmannAngeli JP, Krysko DV, Conrad M. Ferroptosis at the crossroads
of cancer-acquired drug resistance and immune evasion. Nat Rev
Cancer. 2019;19(7):405–14.
133. Huynh K, et al. Diabetic cardiomyopathy: mechanisms and new treat-
ment strategies targeting antioxidant signaling pathways. Pharmacol
Ther. 2014;142(3):375–415.
134. Schulze PC, Drosatos K, Goldberg IJ. Lipid use and misuse by the heart.
Circ Res. 2016;118(11):1736–51.
135. Ritchie RH, et al. Lipid metabolism and its implications for type 1 diabe-
tes-associated cardiomyopathy. J Mol Endocrinol. 2017;58(4):R225-r240.
136. Eid S, et al. New insights into the mechanisms of diabetic com-
plications: role of lipids and lipid metabolism. Diabetologia.
2019;62(9):1539–49.
137. Sharma S, et al. Intramyocardial lipid accumulation in the failing human
heart resembles the lipotoxic rat heart. FASEB J. 2004;18(14):1692–700.
138. Wang S, et al. Ablation of Akt2 prevents paraquat-induced myocardial
mitochondrial injury and contractile dysfunction: role of Nrf2. Toxicol
Lett. 2017;269:1–14.
139. Rashidipour N, et al. Where ferroptosis inhibitors and paraquat detoxi-
fication mechanisms intersect, exploring possible treatment strategies.
Toxicology. 2020;433–434: 152407.
140. Kang R, Tang D. Autophagy and ferroptosis—what’s the connection?
Curr Pathobiol Rep. 2017;5(2):153–9.
141. Hou W, et al. Autophagy promotes ferroptosis by degradation of ferritin.
Autophagy. 2016;12(8):1425–8.
142. Gao M, et al. Ferroptosis is an autophagic cell death process. Cell Res.
2016;26(9):1021–32.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 15 of 16
Yanetal. Diabetology & Metabolic Syndrome (2023) 15:161
143. Torii S, et al. An essential role for functional lysosomes in ferroptosis of
cancer cells. Biochem J. 2016;473(6):769–77.
144. Psaltis PJ, et al. Assessment of myocardial fibrosis by endoventricular
electromechanical mapping in experimental nonischemic cardiomyo-
pathy. Int J Cardiovasc Imaging. 2011;27(1):25–37.
145. Reed AL, et al. Diastolic dysfunction is associated with cardiac fibrosis
in the senescence-accelerated mouse. Am J Physiol Heart Circ Physiol.
2011;301(3):H824–31.
146. Chang WT, et al. Characterization of aging-associated cardiac diastolic
dysfunction. PLoS ONE. 2014;9(5): e97455.
147. Arezzini B, et al. Iron overload enhances the development of experi-
mental liver cirrhosis in mice. Int J Biochem Cell Biol. 2003;35(4):486–95.
148. Pepe A, et al. Myocardial scarring by delayed enhancement car-
diovascular magnetic resonance in thalassaemia major. Heart.
2009;95(20):1688–93.
149. Sampaio AF, et al. Iron toxicity mediated by oxidative stress
enhances tissue damage in an animal model of diabetes. Biometals.
2014;27(2):349–61.
150. Shimizu M, et al. Collagen remodelling in myocardia of patients with
diabetes. J Clin Pathol. 1993;46(1):32–6.
151. Fraga CG, Oteiza PI. Iron toxicity and antioxidant nutrients. Toxicology.
2002;180(1):23–32.
152. Rui W, et al. Compound Astragalus and Salvia miltiorrhiza extract sup-
presses hepatocellular carcinoma progression by inhibiting fibrosis and
PAI-1 mRNA transcription. J Ethnopharmacol. 2014;151(1):198–209.
153. Patel R, et al. Synthetic smooth muscle cell phenotype is associated
with increased nicotinamide adenine dinucleotide phosphate oxidase
activity: effect on collagen secretion. J Vasc Surg. 2006;43(2):364–71.
154. Kumfu S, et al. T-type calcium channel as a portal of iron uptake
into cardiomyocytes of beta-thalassemic mice. Eur J Haematol.
2011;86(2):156–66.
155. Oudit GY, et al. Role of L-type Ca2+ channels in iron transport and iron-
overload cardiomyopathy. J Mol Med (Berl). 2006;84(5):349–64.
156. Sugishita K, et al. A case of iron overload cardiomyopathy: beneficial
effects of iron chelating agent and calcium channel blocker on left
ventricular dysfunction. Int Heart J. 2009;50(6):829–38.
157. Gherasim L, et al. A morphological quantitative study of small vessels in
diabetic cardiomyopathy. Morphol Embryol (Bucur). 1985;31(3):191–5.
158. Di Carli MF, et al. Role of chronic hyperglycemia in the pathogenesis
of coronary microvascular dysfunction in diabetes. J Am Coll Cardiol.
2003;41(8):1387–93.
159. Hansen A, et al. C-peptide exerts beneficial effects on myocardial
blood flow and function in patients with type 1 diabetes. Diabetes.
2002;51(10):3077–82.
160. Joshi MS, et al. Functional relevance of genetic variations of endothe-
lial nitric oxide synthase and vascular endothelial growth factor in
diabetic coronary microvessel dysfunction. Clin Exp Pharmacol Physiol.
2013;40(4):253–61.
161. Kahlberg N, et al. Adverse vascular remodelling is more sensitive than
endothelial dysfunction to hyperglycaemia in diabetic rat mesenteric
arteries. Pharmacol Res. 2016;111:325–35.
162. Ng HH, et al. Serelaxin treatment reverses vascular dysfunction and left
ventricular hypertrophy in a mouse model of Type 1 diabetes. Sci Rep.
2017;7:39604.
163. Chen Y, et al. Isorhapontigenin attenuates cardiac microvascular injury
in diabetes via the inhibition of mitochondria-associated ferroptosis
through PRDX2-MFN2-ACSL4 pathways. Diabetes. 2023;72(3):389–404.
164. Liu Z. Cardiac microvascular dysfunction and cardiomyopathy in diabe-
tes: is ferroptosis a therapeutic target? Diabetes. 2023;72(3):313–5.
165. Guo L, et al. The association of serum vascular endothelial growth factor
and ferritin in diabetic microvascular disease. Diabetes Technol Ther.
2014;16(4):224–34.
166. Mangoni AA. The emerging role of symmetric dimethylarginine in
vascular disease. Adv Clin Chem. 2009;48:73–94.
167. He H, et al. Iron overload damages the endothelial mitochondria via
the ROS/ADMA/DDAHII/eNOS/NO pathway. Oxid Med Cell Longev.
2019;2019:2340392.
168. Millare B, O’Rourke B, Trayanova N. Hydrogen peroxide diffusion and
scavenging shapes mitochondrial network instability and failure by
sensitizing ROS-induced ROS release. Sci Rep. 2020;10(1):15758.
169. Chen X, et al. Quercetin protects the vascular endothelium against iron
overload damages via ROS/ADMA/DDAHII/eNOS/NO pathway. Eur J
Pharmacol. 2020;868: 172885.
170. Park JG, et al. Peroxiredoxin 2 deficiency exacerbates atherosclerosis in
apolipoprotein E-deficient mice. Circ Res. 2011;109(7):739–49.
171. Li D, et al. Ferroptosis and its role in cardiomyopathy. Biomed Pharma-
cother. 2022;153: 113279.
172. Abe K, et al. Doxorubicin causes ferroptosis and cardiotoxicity by
intercalating into mitochondrial DNA and disrupting Alas1-dependent
heme synthesis. Sci Signal. 2022;15(758): eabn8017.
173. Ta N, et al. Mitochondrial outer membrane protein FUNDC2 promotes
ferroptosis and contributes to doxorubicin-induced cardiomyopathy.
Proc Natl Acad Sci USA. 2022;119(36): e2117396119.
174. Wang Z, et al. Exploring the communal pathogenesis, ferroptosis
mechanism, and potential therapeutic targets of dilated cardiomyopa-
thy and hypertrophic cardiomyopathy via a microarray data analysis.
Front Cardiovasc Med. 2022;9: 824756.
175. Jiang Y, et al. Ferroptosis related genes in ischemic and idiopathic
cardiomyopathy: screening for potential pharmacological targets. Front
Cell Dev Biol. 2022;10: 817819.
176. Wong CAC, Leitch HA. Delayed time from RBC transfusion dependence
to first cardiac event in lower IPSS risk MDS patients receiving iron
chelation therapy. Leuk Res. 2019;83: 106170.
177. Philipp S, et al. Desferoxamine and ethyl-3,4-dihydroxybenzoate protect
myocardium by activating NOS and generating mitochondrial ROS. Am
J Physiol Heart Circ Physiol. 2006;290(1):H450–7.
178. Bollig C, et al. Deferasirox for managing iron overload in people with
thalassaemia. Cochrane Database Syst Rev. 2017;8(8):CD07476.
179. Meerpohl JJ, et al. Deferasirox for managing iron overload in people
with thalassaemia. Cochrane Database Syst Rev. 2012;2: CD007476.
180. Song T, Zhang D. Evaluation on curative effects of ethylene diamine
tetra-acetic acid chelation therapy in treating with atherosclerotic car-
diovascular disease: a protocol for systematic review and meta-analysis.
Medicine (Baltimore). 2020;99(52): e23346.
181. Villarruz-Sulit MV, et al. Chelation therapy for atherosclerotic cardiovas-
cular disease. Cochrane Database Syst Rev. 2020;5(5): CD002785.
182. Poggiali E, et al. An update on iron chelation therapy. Blood Transfus.
2012;10(4):411–22.
183. Zhang X, et al. SLC7A11/xCT prevents cardiac hypertrophy by inhibiting
ferroptosis. Cardiovasc Drugs Ther. 2022;36(3):437–47.
184. Zhang Y, et al. Targeting ferroptosis by polydopamine nanoparticles
protects heart against ischemia/reperfusion injury. ACS Appl Mater
Interfaces. 2021;13(45):53671–82.
185. Long Q, et al. SGLT2 inhibitor, canagliflozin, ameliorates cardiac inflam-
mation in experimental autoimmune myocarditis. Int Immunopharma-
col. 2022;110: 109024.
186. Wang X, et al. Canagliflozin prevents lipid accumulation, mitochondrial
dysfunction, and gut microbiota dysbiosis in mice with diabetic cardio-
vascular disease. Front Pharmacol. 2022;13: 839640.
187. Du S, et al. Canagliflozin mitigates ferroptosis and improves myocardial
oxidative stress in mice with diabetic cardiomyopathy. Front Endocrinol
(Lausanne). 2022;13:1011669.
188. Sun P, et al. Canagliflozin attenuates lipotoxicity in cardiomyocytes
and protects diabetic mouse hearts by inhibiting the mTOR/HIF-1α
pathway. IScience. 2021;24(6): 102521.
189. Zhang W, et al. Canagliflozin attenuates lipotoxicity in cardiomyocytes
by inhibiting inflammation and ferroptosis through activating AMPK
pathway. Int J Mol Sci. 2023;24(1):858.
190. Robson A. Lovastatin improves endothelial cell function in LMNA-
related DCM. Nat Rev Cardiol. 2020;17(10):613.
191. Zilka O, et al. On the mechanism of cytoprotection by ferrostatin-1 and
liproxstatin-1 and the role of lipid peroxidation in ferroptotic cell death.
ACS Cent Sci. 2017;3(3):232–43.
192. Ward NC, Watts GF, Eckel RH. Statin toxicity. Circ Res.
2019;124(2):328–50.
193. Bonifacio A, et al. Simvastatin induces mitochondrial dysfunction and
increased atrogin-1 expression in H9c2 cardiomyocytes and mice
in vivo. Arch Toxicol. 2016;90(1):203–15.
194. Godoy JC, et al. Atorvastatin, but not pravastatin, inhibits cardiac Akt/
mTOR signaling and disturbs mitochondrial ultrastructure in cardiac
myocytes. FASEB J. 2019;33(1):1209–25.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 16 of 16
Yanetal. Diabetology & Metabolic Syndrome (2023) 15:161
•
fast, convenient online submission
•
thorough peer review by experienced researchers in your field
•
rapid publication on acceptance
•
support for research data, including large and complex data types
•
gold Open Access which fosters wider collaboration and increased citations
maximum visibility for your research: over 100M website views per year
•
At BMC, research is always in progress.
Learn more biomedcentral.com/submissions
Ready to submit your research
Ready to submit your research
? Choose BMC and benefit from:
? Choose BMC and benefit from:
195. Zhang Q, et al. Atorvastatin induces mitochondria-dependent fer-
roptosis via the modulation of Nrf2-xCT/GPx4 axis. Front Cell Dev Biol.
2022;10: 806081.
196. Wang K, Gheblawi M, Oudit GY. Angiotensin converting enzyme 2: a
double-edged sword. Circulation. 2020;142(5):426–8.
197. Li J, et al. Targeting the Nrf2 pathway against cardiovascular disease.
Expert Opin Ther Targets. 2009;13(7):785–94.
198. Ge ZD, et al. Current status and challenges of NRF2 as a poten-
tial therapeutic target for diabetic cardiomyopathy. Int Heart J.
2019;60(3):512–20.
199. Zhang H, et al. Gypenosides improve diabetic cardiomyopathy by
inhibiting ROS-mediated NLRP3 inflammasome activation. J Cell Mol
Med. 2018;22(9):4437–48.
200. Sharma A, et al. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2)
activator dh404 protects against diabetes-induced endothelial dysfunc-
tion. Cardiovasc Diabetol. 2017;16(1):33.
201. Wang J, et al. Protection against diabetic cardiomyopathy is achieved
using a combination of sulforaphane and zinc in type 1 diabetic OVE26
mice. J Cell Mol Med. 2019;23(9):6319–30.
202. Guan Y, et al. Effects of PP2A/Nrf2 on experimental diabetes mellitus-
related cardiomyopathy by regulation of autophagy and apoptosis
through ROS dependent pathway. Cell Signal. 2019;62: 109339.
203. Wang Z, et al. Dexmedetomidine attenuates myocardial ischemia/
reperfusion-induced ferroptosis via AMPK/GSK-3β/Nrf2 axis. Biomed
Pharmacother. 2022;154: 113572.
204. Yu P, et al. Dexmedetomidine post-conditioning alleviates myocar-
dial ischemia–reperfusion injury in rats by ferroptosis inhibition via
SLC7A11/GPX4 axis activation. Hum Cell. 2022;35(3):836–48.
205. Song C, et al. Berberine hydrochloride alleviates imatinib mesylate-
induced cardiotoxicity through the inhibition of Nrf2-dependent
ferroptosis. Food Funct. 2023;14(2):1087–98.
206. Yang KT, et al. Berberine protects cardiac cells against ferroptosis. Tzu
Chi Med J. 2022;34(3):310–7.
207. Lu H, et al. Britanin relieves ferroptosis-mediated myocardial ischaemia/
reperfusion damage by upregulating GPX4 through activation of
AMPK/GSK3β/Nrf2 signalling. Pharm Biol. 2022;60(1):38–45.
208. Mei SL, et al. Shenmai injection attenuates myocardial ischemia/reper-
fusion injury by targeting Nrf2/GPX4 signalling-mediated ferroptosis.
Chin J Integr Med. 2022;28(11):983–91.
209. Wu S, et al. 6-Gingerol alleviates ferroptosis and inflammation of
diabetic cardiomyopathy via the Nrf2/HO-1 pathway. Oxid Med Cell
Longev. 2022;2022:3027514.
210. Wei Z, et al. Curcumin attenuates ferroptosis-induced myocardial injury
in diabetic cardiomyopathy through the Nrf2 pathway. Cardiovasc Ther.
2022;2022:3159717.
211. Uruno A, et al. The Keap1-Nrf2 system prevents onset of diabetes mel-
litus. Mol Cell Biol. 2013;33(15):2996–3010.
212. Xu J, et al. Enhanced Nrf2 activity worsens insulin resistance, impairs
lipid accumulation in adipose tissue, and increases hepatic steatosis in
leptin-deficient mice. Diabetes. 2012;61(12):3208–18.
213. Zang H, Mathew RO, Cui T. The dark side of Nrf2 in the heart. Front
Physiol. 2020;11:722.
214. Shi J, et al. Gut microbiota profiling revealed the regulating effects
of salidroside on iron metabolism in diabetic mice. Front Endocrinol
(Lausanne). 2022;13:1014577.
215. Chen H, et al. Salidroside inhibits doxorubicin-induced cardiomyopa-
thy by modulating a ferroptosis-dependent pathway. Phytomedicine.
2022;99: 153964.
216. You J, et al. Discovery of 2-vinyl-10H-phenothiazine derivatives as
a class of ferroptosis inhibitors with minimal human Ether-a-go-go
related gene (hERG) activity for the treatment of DOX-induced cardio-
myopathy. Bioorg Med Chem Lett. 2022;74: 128911.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1.
2.
3.
4.
5.
6.
Terms and Conditions
Springer Nature journal content, brought to you courtesy of Springer Nature Customer Service Center GmbH (“Springer Nature”).
Springer Nature supports a reasonable amount of sharing of research papers by authors, subscribers and authorised users (“Users”), for small-
scale personal, non-commercial use provided that all copyright, trade and service marks and other proprietary notices are maintained. By
accessing, sharing, receiving or otherwise using the Springer Nature journal content you agree to these terms of use (“Terms”). For these
purposes, Springer Nature considers academic use (by researchers and students) to be non-commercial.
These Terms are supplementary and will apply in addition to any applicable website terms and conditions, a relevant site licence or a personal
subscription. These Terms will prevail over any conflict or ambiguity with regards to the relevant terms, a site licence or a personal subscription
(to the extent of the conflict or ambiguity only). For Creative Commons-licensed articles, the terms of the Creative Commons license used will
apply.
We collect and use personal data to provide access to the Springer Nature journal content. We may also use these personal data internally within
ResearchGate and Springer Nature and as agreed share it, in an anonymised way, for purposes of tracking, analysis and reporting. We will not
otherwise disclose your personal data outside the ResearchGate or the Springer Nature group of companies unless we have your permission as
detailed in the Privacy Policy.
While Users may use the Springer Nature journal content for small scale, personal non-commercial use, it is important to note that Users may
not:
use such content for the purpose of providing other users with access on a regular or large scale basis or as a means to circumvent access
control;
use such content where to do so would be considered a criminal or statutory offence in any jurisdiction, or gives rise to civil liability, or is
otherwise unlawful;
falsely or misleadingly imply or suggest endorsement, approval , sponsorship, or association unless explicitly agreed to by Springer Nature in
writing;
use bots or other automated methods to access the content or redirect messages
override any security feature or exclusionary protocol; or
share the content in order to create substitute for Springer Nature products or services or a systematic database of Springer Nature journal
content.
In line with the restriction against commercial use, Springer Nature does not permit the creation of a product or service that creates revenue,
royalties, rent or income from our content or its inclusion as part of a paid for service or for other commercial gain. Springer Nature journal
content cannot be used for inter-library loans and librarians may not upload Springer Nature journal content on a large scale into their, or any
other, institutional repository.
These terms of use are reviewed regularly and may be amended at any time. Springer Nature is not obligated to publish any information or
content on this website and may remove it or features or functionality at our sole discretion, at any time with or without notice. Springer Nature
may revoke this licence to you at any time and remove access to any copies of the Springer Nature journal content which have been saved.
To the fullest extent permitted by law, Springer Nature makes no warranties, representations or guarantees to Users, either express or implied
with respect to the Springer nature journal content and all parties disclaim and waive any implied warranties or warranties imposed by law,
including merchantability or fitness for any particular purpose.
Please note that these rights do not automatically extend to content, data or other material published by Springer Nature that may be licensed
from third parties.
If you would like to use or distribute our Springer Nature journal content to a wider audience or on a regular basis or in any other manner not
expressly permitted by these Terms, please contact Springer Nature at
onlineservice@springernature.com