Biomedicine & Pharmacotherapy 176 (2024) 116815

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Review

The crosstalk between cell death and pregnancy related diseases: A

narrative review
Xiaowen Xie a, b, 1, Jiayu Liu c, 1, Jingyi Gao d, 1, Chenwei Shang a, e, Ying Jiang c, Lingyan Chen a,
Zhiwen Qian a, Lu Liu c, Danping Wu c, Yun Zhang f, *, Zhu Ru g, **, Yan Zhang c, a, ***
a
Wuxi Maternal and Child Health Hospital, Wuxi Medical Center of Nanjing Medical University, Wuxi, Jiangsu 214002, China
b
The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu
214023, China
c
Department of Oncology, Wuxi Maternal and Child Health Care Hospital, Affiliated Women’s Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu
214002, China
d
Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China
e
The First Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu 210029, China
f
Wuxi Maternal and Child Health Care Hospital, Affiliated Women’s Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu 214002, China
g
Anqing Medical College Clinical Research Center, Anqing Municipal Hospital, Anqing 246003, Anhui, China

Abbreviations: AIF, apoptosis-inducing factor; AIM2, absent in melanoma 2; AKT, protein kinase B; AMP, adenosine monophosphate; AMPK, AMP-activated
protein kinase; APAF-1, apoptotic protease activator factor-1; ASC, apoptosis-associated speck-like protein containing CARD; ASK1, apoptosis signal-rgulating kinase
1; ATF, activating transcription factor; ATG, autophagy-related gene; ATP, adenosine triphosphate; BAK, BCL-2-associated k protein; BAX, BCL-2-associated X
protein; BCL-2, B cell lymphoma-2; BH3, BCL-2 homology region 3; BID, BH3-interacting domain death agonist; Bim, Bcl-2-Like Protein 11; CFLIP, cellular caspase-8
FLICE-like inhibitory protein; CHOP, C/EBP-homologous protein; CYLD, cylindromatosis; DAMPs, damage associated molecular patterns; DISC, death-inducing
signaling complex; DMT1, divalent metal transporter 1; DsDNA, double-stranded DNA; Elf2α, eukaryotic initiation factor-2α; Endo G, endonuclease G; ER, endo­
plasmic reticulum; ERK, extracellular regulated protein kinases; ERp29, endoplasmic reticulum protein 29; EVTs, extravillous trophoblasts; FADD, Fas-associating
protein with a novel death domain; FGR, fetal growth restriction; FIP200, focal adhesion kinase family interacting protein of 200 kD; FOXO3, forkhead box O3; FTL,
ferritin light chain; GCDCA, glycochenodeoxycholic acid; GDM, gestational diabetes mellitus; Glu, glutamicacid; GLUT, glucose transporter; GPX4, glutathione
peroxidase 4; GSDMD/E, gasdermin D/E; GSH, glutathione; Hcy, homocysteine; HDACs,, histone deacetylases; HIF-1α, hypoxia inducible factor-1α; HTRA, high-
temperature requirement serine protease A; ICP, intrahepatic cholestasis of pregnancy; IL-34, interleukin-34; IRE1, inositol-requiring enzyme 1; IUGR,, intra-uterine
growth restriction; JNK, c-Jun N-terminal protein kinase; LC3, microtubule-associated protein light chain 3; LncRNAs, long non-coding RNAs; LPS, lipopolysac­
charides; MLKL, mixed lineage kinase domain-like proteins; MOMP, mitochondrial outer membrane permeabilization; MTOR, mammalian target of rapamycin;
MTORC1, mammalian target of rapamycin complex 1; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor-κB; NINJ1, ninjurin 1; NLRC4,
NLR family CARD domain containing 4; NLRP3, NOD-like receptor family, pyrin domain-containing protein 3; P38 MAPK, p38 mitogen-activated protein kinases;
PAMPs, pathogen-associated molecular patterns; PI3K, phosphatidylinositol 3-kinase; Pe, phosphatidylethanolamine; PE, preeclampsia; PERK, protein kinase RNA-
like endoplasmic reticulum kinase; PLOOHs, phospholipid hydroperoxides; PPARγ, peroxisome proliferator-activated receptor γ; PUFAs, polyunsaturated fatty acids;
RIPK, receptor-interacting protein kinase; RM, recurrent miscarriage; ROS, reactive oxygen species; RPL, recurrent pregnancy loss; RSA, recurrent spontaneous
abortion; RTK, receptor tyrosine kinase; SENG, soluble endothelial glycoprotein; SETD7, SET domain containing lysine methyltransferase 7; SIRT, silent information
regulator factor 2-related enzyme; SMAC, second mitochondria-derived activator of caspases; STAPA2, spermatogenesis-associated protein 2; STAT1, signal trans­
ducer and activator of transcription 1; STEAP3, six-transmembrane epithelial antigen of prostate 3; TFR, transferrin receptor; TLR, toll-like receptors; TNFL, tumor
necrosis factor ligand; TNFR, tumor necrosis factor receptor; TRADD, tumor necrosis factor receptor type 1-associated death domain protein; TRAF, tumor necrosis
factor receptor-associated factor; TRAIL, TNF-related apoptosis-inducing ligand; TRIB3, tribbles3; TRIF, TIR domain-containing adaptor inducing interferon-β; TSC1/
2, tuberous sclerosis complex 1/2; TBID, truncated BH3-interacting domain death agonist; ULK1, unc-51-like kinase 1; UPR, unfolded protein response; VEGF,
vascular endothelial growth factor; VPS34, vacuolar protein sorting 34; XIAP, X chromosome-linked inhibitor of apoptosis protein; ZBP1, Z-conformation nucleic acid
binding protein 1; ZIKV, zika virus.
* Correspondenc to: Wuxi Maternal and Child Health Care Hospital,Wuxi School of Medicine, Jiangnan University, No. 48 Huaishu Road, Wuxi, Jiangsu 214002,
China.
** Correspondence to: Anqing Medical College Clinical Research Center, Anqing Municipal Hospital, No. 87 Tianzhushan East Road, Anqing, Anhui 246003, China.
*** Correspondence to: Department of Oncology, Wuxi Maternal and Child Health Care Hospital,Wuxi School of Medicine, Jiangnan University, No. 48 Huaishu
Road, Wuxi, Jiangsu 214002, China.
E-mail addresses: zhangyun2107@163.com (Y. Zhang), zhuru19790202@163.com (Z. Ru), fuyou2007@126.com (Y. Zhang).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.biopha.2024.116815
Received 26 March 2024; Received in revised form 10 May 2024; Accepted 21 May 2024
Available online 23 May 2024
0753-3322/© 2024 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
X. Xie et al. Biomedicine & Pharmacotherapy 176 (2024) 116815

A R T I C L E I N F O A B S T R A C T

Keywords: Programmed cell death is intricately linked to various physiological phenomena such as growth, development,
Cell death and metabolism, as well as the proper function of the pancreatic β cell and the migration and invasion of
Pregnancy related disease trophoblast cells in the placenta during pregnancy. Traditional and recently identified programmed cell death
Apoptosis
include apoptosis, autophagy, pyroptosis, necroptosis, and ferroptosis. In addition to cancer and degenerative
Autophagy
Pyroptosis
diseases, abnormal activation of cell death has also been implicated in pregnancy related diseases like pre­
Necroptosis eclampsia, gestational diabetes mellitus, intrahepatic cholestasis of pregnancy, fetal growth restriction, and
Ferroptosis recurrent miscarriage. Excessive or insufficient cell death and pregnancy related diseases may be mutually
determined, ultimately resulting in adverse pregnancy outcomes. In this review, we systematically describe the
characteristics and mechanisms underlying several types of cell death and their roles in pregnancy related dis­
eases. Moreover, we discuss potential therapeutic strategies that target cell death signaling pathways for preg­
nancy related diseases, hoping that more meaningful treatments will be applied in clinical practice in the future.

1. Introduction interventions. To explore the roles of diverse cell death in pregnancy

Cell death refers to irreversible changes such as metabolic arrest,
structural destruction, and functional deterioration following severe
cellular damage. Formerly perceived as stemming from either apoptosis
or necrosis, recent discoveries have unveiled several novel modes of cell
death, each with distinct pathways [1]. Different types of cell death
exhibit diverse characteristics. For instance, as an enzyme-dependent
biochemical process, apoptosis performs in a controlled manner, with
cellular contents mostly removed by tissue-resident professional
phagocytes or neighboring non-professional phagocytes instead of being
spilled over into the extracellular milieu [2]. On the contrary, necrosis is
commonly described as uncontrolled cell death, typically accompanied
by a severe invasion, leading to linkage of cellular contents and subse­
quent impairment [1]. Interestingly, necroptosis displays the features of
necrosis but is tightly regulated, resembling a highly regulated form of
necrosis [3].
The dysregulation of cell death has been implicated in a range of
diseases. Overactivation of cell death increases the susceptibility to
neurodegenerative diseases, whereas deficits in cell death are associated
with tumors and autoimmune diseases [4–6]. The placenta serves as a
bridge between mother and fetus, facilitating material exchange, hor­
monal regulation, defense against pathogens, and immune tolerance
maintenance. These types of cell death also exert pivotal roles in both
the physiological development and abnormal disorders of the placenta
and the fetus. Apoptosis contributes to the placenta’s growth through
providing efficient utero-placental blood perfusion to the early fetus [7].
The number of apoptotic cells in the placenta fluctuates throughout
gestational stages. Apoptosis in the placenta mostly occurs in syncytio­
trophoblasts, which act as a barrier between fetal and maternal circu­
lation and are essential for maintaining placental homeostasis [8].
Intrahepatic cholestasis of pregnancy (ICP) results in elevated bile acid
levels and prolonged exposure to toxic bile acids, thereby compromising
trophoblast cell function and impairing autophagic processes. [9].
Furthermore, increased placental size and mass in gestational diabetes
mellitus (GDM) correlate with a considerable reduction in trophoblast
apoptosis [10,11]. Nutritional deficiencies during pregnancy may
weaken defenses against environmental pollutants and precipitate
changes in the body’s internal environment, fostering apoptosis, ne­
crosis, and other aberrant cell deaths, leading to abnormal invasion of
the trophoblast and the development of preeclampsia (PE) [12]. In
addition, placental cells are extremely sensitive to ferroptosis. Factors
such as hypoxia or reactive oxygen species (ROS) injury can all indi­
rectly induce placental ferroptosis [13].
Previous reviews have tended to focus on the connections between
cell death and cancer and degenerative diseases, or single cell death in
pregnancy related diseases, but there are few comprehensive reviews of
the relationship between various forms of cell death and pregnancy
related diseases. Our review aims to fill the gap in this field and provide
reference and guidance for both basic research and clinical
related diseases, we collated a large amount of literature and found that
apoptosis, autophagy, necroptosis, pyroptosis, and ferroptosis are the
main cell death modes affecting pregnancy related diseases. Based on
the keywords of five cell death and pregnancy related diseases, we
conducted a thorough search of recent literature, filtering out works of
significant relevance and high quality. Subsequently, we meticulously
analyzed, organized, and summarized these findings (Fig. 1A). In this
review, we centered on these five cell death modes that have been
deeply implicated in pregnancy related diseases. We elaborated their
respective mechanisms of action that might induce pregnancy related
diseases, particularly PE, ICP, and GDM. The impacts of these cell death
modes on pregnancy related diseases were also described. At the same
time, we summarized multiple ways in which cell death can exert pos­
itive effects or inhibit the deterioration of pregnancy related diseases,
presenting several cell death-related treatment approaches that may
transform the therapeutic landscape (Fig. 1B).
2. Apoptosis
2.1. Mechanisms of apoptosis
Apoptosis refers to the self-regulated and systematic cell death
controlled by genes to maintain a stable internal environment. In 1972,
Kerr, Wyllie, and Currie first proposed the concept of “apoptosis,”
describing its morphological features as cellular shrinkage, membrane
blebbing, nuclear fragmentation, chromatin condensation, and the for­
mation of apoptotic body [14]. In general, apoptosis can be triggered
through three pathways: the intrinsic pathway, the extrinsic pathway,
and the endoplasmic reticulum stress (ER stress)-induced pathway
(Fig. 2).
The intrinsic pathway, also known as the mitochondrial pathway of
apoptosis, is initiated by intracellular stressors [15]. Once the cell per­
ceives these stressors, mitochondrial outer membrane permeabilization
(MOMP) will occur, leading to cytochrome c releasing from the inter­
membrane space of mitochondria into the cytosol [16]. In this process,
proapoptotic proteins of the B cell lymphoma-2 (BCL-2) family, promi­
nently BCL-2-associated X protein (BAX) and BCL-2-associated k protein
(BAK), and dynamin-related protein 1-induced cristae remodeling play a
crucial role [17,18]. At the same time, BCL-2 homology region 3
(BH3)-only proteins directly target BAX/BAK or deactivate
anti-apoptotic BCL-2 proteins to trigger apoptosis [19]. Subsequently,
cytochrome c attaches to apoptotic protease activator factor-1 (APAF-1)
monomers, prompting the conformational shift in APAF-1 and its
interaction with procaspase-9, thus forming the apoptosome, where
activated caspase-9 cleaves the precursors of caspase-3 and -7 and un­
leashes their apoptotic executioner function [20,21]. X
chromosome-linked inhibitor of apoptosis protein (XIAP) prevents pro­
cessed caspase activity to elevate the threshold for apoptosis activation
[22]. However, second mitochondria-derived activator of caspases

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X. Xie et al. Biomedicine & Pharmacotherapy 176 (2024) 116815

(SMAC) and high-temperature requirement serine protease A2 (HTRA2),
co-released with cytochrome c during MOMP, serve as XIAP inhibitors
[23].
The extrinsic pathway, also called the death receptor pathway of
apoptosis, begins with the binding of death ligands to death receptors
[24]. Once the combination happens, adapter proteins tumor necrosis
factor receptor type 1-associated death domain protein (TRADD) or
Fas-associating protein with a novel death domain (FADD) and initiator
procaspases (procaspase-8 and -10) will be recruited, resulting in the
assembly of the death-inducing signaling complex (DISC) [25]. In Type I
cells, activated caspase-8 directly activates the executioner caspases,
while in Type II cells, caspase-8 cleaves the BH3-interacting domain
death agonist (BID) to truncated BID (tBID), which enters mitochondria
and activates the intrinsic apoptotic pathway [26]. Meanwhile, the
anti-apoptotic protein cellular caspase-8 (FLICE)-like inhibitory protein
(cFLIP) can suppress the activity of caspase-8 [27].
Endoplasmic reticulum secretory failure, infections, hypoxia, and
several chemicals can all trigger the buildup of unfolded or misfolded
proteins, which induces ER stress-induced cell death [16]. Unfolded
protein response (UPR) pathway, initiated by protein misfolding, has
three main ingredients: inositol-requiring enzyme 1 (IRE1), protein ki­
nase RNA-like endoplasmic reticulum kinase (PERK), and activating
transcription factor 6 (ATF6), all of which can induce apoptosis through
activating C/EBP-homologous protein (CHOP) [28,29]. In short, the
equilibrium between pro-apoptotic and anti-apoptotic factors ensures
the normal progress of apoptosis.
2.2. Apoptosis in pregnancy related diseases
2.2.1. Apoptosis in PE
PE, one of the most fearful complications of pregnancy, frequently
manifests as new-onset hypertension, proteinuria, or other end-organ
damage during the third trimester, threatening the life safety of both
mother and fetus [30]. Although the precise pathogenesis remains
incompletely elucidated, it is known that abnormal spiral artery
remodeling and inadequate trophoblast invasion are closely related to
PE [31]. In addition, inflammation and increased apoptosis in villous
cytotrophoblasts during early pregnancy augment the risk of PE [32]. In
the placenta of patients with PE, highly expressed IFN-γ upregulates the
phosphorylation levels of Janus kinase 1 and signal transducer and
activator of transcription 1 (STAT1) to inhibit the migration and inva­
sion of trophoblast cells while promoting apoptosis [33]. Furthermore,
oxidative stress is associated with the pathogenesis of PE. Increased
sensitivity to apoptosis has been observed in chorionic trophoblast cells

Fig. 1. A brief overview of cell death and pregnancy related diseasesA. From the articles we obtained and screened, we summarized the five modes of cell death most
closely related to pregnancy related diseases, which may be involved in adverse pregnancy outcomes. B. Stressors present in the environment and in the body of
pregnant women lead to the dysregulation of cell death in some tissues and organs, thereby becoming a potential cause of pregnancy related diseases. Meanwhile,
pregnancy related diseases can further exacerbate the dysregulation of cell death.

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in the placentas of pregnant women with intra-uterine growth restric­
tion (IUGR) and PE, which makes trophoblast cells more susceptible to
oxidative damage [34,35]. Evidence suggests that excessive placental
ROS activate p38 MAPK and nuclear factor-κB (NF-κB) pathways,
incurring trophoblast apoptosis [36]. As a nicotinamide adenine
dinucleotide-dependent histone deacetylase, SIRT1 controls apoptosis
and autophagy via deacetylating its downstream targets. Elevated
intracellular ROS levels weaken the activity of SIRT1 in PE placentas,
resulting in dysregulation of apoptosis [37]. Moreover, studies have
demonstrated that an imbalance in micronutrients such as folate and
vitamin B12 causes oxidative stress and higher homocysteine levels,
which gives rise to increased placental apoptosis and changes in
placental angiogenesis [38]. The complement system is fundamental to
the clearance of apoptotic cells, but the reaction can be inflammatory in
PE, increasing the risk of pregnancy complications and impaired endo­
thelial integrity [39]. What’s more, dysregulation of certain genes or
long non-coding RNAs (lncRNAs) also has an impact on trophoblast
invasion and apoptosis [40,41]. For example, lncRNA BNIP3P1 targets
the miR-128–3p/BCL2 Interacting Protein 3/mammalian target of
rapamycin (mTOR) signaling pathway to inhibit trophoblast cell pro­
liferation and facilitate cell apoptosis in PE [42].
2.2.2. Apoptosis in intrahepatic cholestasis of pregnancy
ICP presents with pruritus, right upper quadrant pain, sleep depri­
vation, and increased serum bile acids and liver transaminases during
the second and third trimesters, related to preterm birth, respiratory
distress syndrome, and fetal demise [43]. Evidence indicates that
placental apoptosis induced by high concentrations of bile acids may be
the major pathological event of ICP and injure the structure and function
of the placenta, ultimately leading to undesirable fetal outcomes [44].
MiRNAs are small noncoding RNA molecules that inhibit the expression
of downstream genes by binding to the target mRNA and are implicated
in various human diseases [45]. According to recent studies, several
exosome miRNAs may serve as novel biomarkers to improve the diag­
nosis and prognosis of ICP [46]. Additionally, it is speculated that
miR-221/222 may increase apoptosis in HTR-8 cells through

Fig. 2. Apoptosis signaling pathway in pregnancy related diseases.The main components of apoptosis include the intrinsic pathway, the extrinsic pathway, and the
ER stress-induced pathway. In the intrinsic pathway, intracellular stressors such as DNA damage and toxic agents activate BAX and BAK, and then boost MOMP. This
process results in the release of cytochrome c and the formation of the apoptosome, subsequently activating caspase-9 and initiating the caspase-processing cascade.
The extrinsic pathway is triggered by the interaction between death ligands and death receptors, which contributes to the formation of DISC and caspase-8 activation,
thereby initiating an amplifying cascade. ER stress also mediates apoptosis through multiple pathways. Several stressors (i.e., ROS, some microRNAs, nutrient
deprivation, and environmental pollutants) associated with pregnancy related diseases participate in apoptosis at different sites, leading to the occurrence of diseases
and promoting disease progression.(AIF, apoptosis-inducing factor; Endo G, endonuclease G; Bim, Bcl-2-Like Protein 11; Hcy, homocysteine; TNFL, tumor necrosis
factor ligand; TNFR, tumor necrosis factor receptor; TRAIL, TNF-related apoptosis-inducing ligand; SIRT1, silent information regulator factor 2-related enzyme 1;
ASK1, apoptosis signal-rgulating kinase 1; JNK, c-Jun N-terminal protein kinase; p38 MAPK, p38 mitogen-activated protein kinases; elf2α, eukaryotic initiation
factor-2α; ATF4, activating transcription factor 4; TRIB3, tribbles3; AKT, protein kinase B).

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X. Xie et al.
downregulating the expression of BCL-2 [47]. Has_circ_0060731
potentially modulates trophoblast cell apoptosis via the
miR-21–5p-PDCD4/ESR1 axis [48]. Endoplasmic reticulum protein 29
(ERp29) influences the biosynthesis of various secretory proteins as well
as apoptosis and oxidative stress regulation [44,49]. Data show that
overexpression of ERp29 induces apoptosis in response to elevated bile
acid concentrations in vitro [50]. Furthermore, ER stress-mediated
trophoblast apoptosis may have a crucial role in the pathogenesis of
ICP, as a study has demonstrated that deoxycholic acid can induce
apoptosis by promoting the expression of mRNA and proteins encoded
by ER stress-related genes in trophoblasts in a concentration-dependent
manner [51]. Animal experiments have also shown severe fetal
myocardial structure damage and increased apoptosis in ICP patients
[52].
2.2.3. Apoptosis in GDM
GDM is a typical pregnancy complication characterized by abnormal
maternal glucose metabolism and is concerned with higher risks of
preterm birth, fetal macrosomia, and neonatal respiratory distress syn­
drome [53]. Neutrophil extracellular traps triggered by hyperglycemia
cause trophoblast apoptosis through the generation of intracellular ROS
and downregulation of extracellular regulated protein kinases (ERK)
pathway [54]. However, another study has found that GDM reduces
apoptosis of the placenta in term [10]. Additionally, lncRNAs have a
place in GDM, similar to their involvement in PE and ICP. By targeting
specific cellular molecules and signaling pathways, certain up-regulated
miRNAs in GDM patients can attenuate cell viability, reduce prolifera­
tion, and promote the apoptosis of pancreatic β cells, thereby compro­
mising pancreatic β cell function [55–57]. Several cardio-protective
miRNAs which prevent cardiomyocyte apoptosis are revealed to be
upregulated in serum from GDM during the first trimester of pregnancy
but considerably suppressed in the third trimester [58]. Besides, it has
been noted that GDM and inflammation have a substantial relationship.
According to studies, interleukin-34 (IL-34) accelerates pancreatic
apoptosis in GDM patients by encouraging STAT3 phosphorylation
through colony-stimulating factor 1 receptor, and it may be secreted into
the fetal circulation, influencing fetus metabolism [59].
2.2.4. Apoptosis in fetal growth restriction
Fetal growth restriction (FGR), also known as IUGR, refers to a
sonographic estimated fetal weight below the 10th percentile or the
abdominal circumference below the 10th percentile, causing secondary
diseases in adulthood and an increased risk of metabolic syndrome [60].
Due to increased syncytiotrophoblast apoptosis, the placenta in FGR
exhibits both damage and healing, along with villus dysplasia [61].
Environmental pollutants, such as heavy metal cadmium, can build up in
the body, resulting in placental apoptosis and FGR through the degra­
dation of myeloid cell leukemia-1 mediated by mitochondrial ROS [62].
MiRNA such as miR-1227–3p is downregulated in the FGR patients’
placentas, yet it may contribute to tumor formation by preventing
apoptosis and boosting cell proliferation and survival [63]. In addition,
the placenta-specific 1 gene related to pregnancy and placental devel­
opment and antiapoptotic BCL-2 gene present reduced expression in
FGR tissues, diminishing their capacity to inhibit trophoblast cell
apoptosis at low oxygen concentrations [64,65].
2.2.5. Apoptosis in recurrent miscarriage
The definition of recurrent miscarriage (RM) is controversial, but it is
evident that RM correlates with long-term health problems extending
beyond pregnancy, and one of the primary factors of RM is trophoblast
function dysregulation [66]. High levels of sprouty 4 may upregulate
IFN-γ/phosphatidylinositol 3-kinase (PI3K)/AKT-induced STAT1 acti­
vation, contributing to the onset and advancement of RM [67]. In
first-trimester RM patients, cyclin A2 downregulation affects the cell
cycle and inhibits HTR8 apoptosis via the p53 pathway [68]. Moreover,
macrophages are typically regarded as necessary for pregnancy
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Biomedicine & Pharmacotherapy 176 (2024) 116815
maintenance [69]. Studies indicate that disruption of
macrophage-induced, FasL-mediated apoptosis may contribute to RM
[70]. Histone deacetylases (HDACs), known as histone modification
enzymes, are crucial for the differentiation, activation, and apoptosis of
various immune cells, including macrophages. Knockdown of HDAC8 in
decidual macrophages from RM patients results in suppressed M2 acti­
vation, and differentiated THP-1 macrophages are more likely to un­
dergo apoptosis through activating the ERK pathway [71].
3. Autophagy
3.1. Mechanisms of autophagy
Autophagy is a process of degradation and regeneration in cells,
which encapsulates damaged or excess cellular components into vesicles
and decomposes them for reuse, akin to fallen petals transforming into
soil to nourish the flower [72]. Autophagy can induce cell death by
initiating apoptosis or through independent pathways [73].
Several stresses, including oxidative stress, nutritional scarcity, and
UPR, can trigger the self-protection mechanism of autophagy [8]. The
signaling pathways are determined by several autophagy-associated
proteins. Unc-51-like kinase 1 (ULK1), focal adhesion kinase family
interacting protein of 200 kD (FIP200), autophagy-related gene 13
(ATG13), and ATG101 collaborate to form a preinitiation complex and
initiate this pathway. The activity of the ULK complex is directly regu­
lated by the mammalian target of rapamycin complex 1 (mTORC1) and
AMP-activated protein kinase (AMPK) [74]. mTOR, a highly conserved
mitogen-activated protein kinase, binds with multiple companion pro­
teins to form distinct signaling complexes, such as mTORC1. mTORC1
inhibits the activity of ULK complexes by phosphorylation and regulates
the expression and function of other key proteins for autophagy, thereby
restraining autophagy [75]. By contrast, triggered by ATP depletion or
metabolic stress, AMPK encourages the initiation of autophagy through
direct and indirect pathways [76]. Therefore, mTOR can be negatively
regulated to promote autophagy, while AMPK plays an antagonistic role
against mTOR. Afterwards, the vacuolar protein sorting 34 (VPS34)
complex, activated by the ULK complex, cooperates with the ULK
complex to promote the creation of autophagosomes [77]. Finally,
autophagosomes combine with lysosomes to form autolysosomes, where
the contents are degraded by proteases derived from lysosomes (Fig. 3)
[1].
3.2. Autophagy in pregnancy related diseases
3.2.1. Autophagy in PE
The pathogenesis of PE remains poorly understood, but many studies
have indicated that the development of PE is related to placental
dysfunction [78]. Under hypoxic conditions, although the standard of
cell viability and proliferation remain similar, the depth of invasion of
extravillous trophoblasts (EVTs) cell lines is significantly shallower
compared to normal, which may be attributed to the inhibition of
autophagy by soluble endothelial glycoprotein (sENG) in EVTs [79]. At
the same time, activated transcription factor hypoxia inducible factor-1α
(HIF-1α) promotes the production of ROS, stimulating the placenta to
release sENG, which further hinders the formation of blood vessels and
aggravates placental hypoxia, thus exacerbating placental dysfunction
[80,81]. A study demonstrated that activation of autophagy in placental
trophoblasts prevents bisphenol A-induced apoptosis and mitochondrial
dysfunction, reducing the risk of pregnancy-related diseases including
PE [82]. Furthermore, through deacetylating several substrates, SIRT1
may promote trophoblast autophagy, thereby providing protection
against PE [83]. However, excessive autophagy induced by long-term
hypoxia can disrupt trophoblast cell invasion and vascular remodel­
ing, impairing placental function [84]. Autophagy activation mediated
by ceramide and hydrolase activity induced by oxidative stress impairs
placental function in PE patients [85]. AMPKα phosphorylation
X. Xie et al. Biomedicine & Pharmacotherapy 176 (2024) 116815

Fig. 3. Autophagy signaling pathway in pregnancy related diseases.Growth factors like insulin and VEGF bind to RTKs on cell membranes, activating the PI3K-AKT-
mTOR pathway, which promotes the absorption and utilization of nutrients such as glucose. Deficiencies in nutrition, ATP, and oxygen activate AMPK, which in turn
activates ULK1 through direct phosphorylation or inhibiting mTOR. The ULK complex works with VPS34 complex to promote phagophore transforming into
autophagosomes under the regulation of Atg5-Atg12-Atg16L and LC3-II. Finally, autophagosomes merge with lysosomes to digest and break down the inner contents.
Pregnancy related diseases are often accompanied by autophagy disorders, such as hyperactivation of autophagy induced by trophoblast cell hypoxia. Overactivation
of autophagy can disrupt cellular metabolic regulation, leading to the onset of diseases.(VEGF, vascular endothelial growth factor; RTK, receptor tyrosine kinase;
AMP, adenosine monophosphate; ATP, adenosine triphosphate; TSC1/2, tuberous sclerosis complex 1/2; LC3, microtubule-associated protein light chain 3; pe,
phosphatidylethanolamine).

decreases the expression of peroxisome proliferator-activated receptor γ
(PPARγ), which is instrumental in regulating spiral artery development
and placental function and is associated with the onset of PE [84,86]. In
conclusion, autophagy is a double-edged sword for PE. In the hypoxic
environment, autophagy plays a pivotal role in early placental growth
and development, whereas insufficient or unduly activation of auto­
phagy can compromise the function of placenta.
3.2.2. Autophagy in ICP
Patients with ICP frequently have elevated levels of bile acids, which
impede autophagy in trophoblasts [9]. Bile acids activate the nuclear
receptor farnesoid X receptor, which is predominantly expressed in the
liver and is thought to inhibit autophagy, resulting in decreased auto­
phagy activity in hepatocytes [87]. Farnesoid X receptor-dependent
Rubicon, an inhibitor of autophagosome maturation, interferes with
the combination of autophagosome and lysosomal, hindering the proper
breakdown of autophagosomes [88]. As a result, autophagy fails to exert
its protective role, disrupting cellular homeostasis and further contrib­
uting to hepatocyte damage in cholestasis. Research has found that bile
acids exert different effects on autophagy under different circumstances.
Glycochenodeoxycholate was once believed to induce autophagy in
hepatocellular carcinoma, while glycochenodeoxycholic acid (GCDCA)
has been discovered to inhibit the formation of autophagosomes and
impair lysosomal function by controlling lysosomal proteolysis and
increasing lysosomal pH in cholestasis [89,90]. Transcription factor E3,
belonging to the same family of transcription factors as transcription
factor EB and interacting with transcription factor EB in the regulation
of autophagy and lysosomal biogenesis, experiences signaling disruption
by GCDCA [91]. Consequently, abnormalities in autophagy activity
caused by the accumulation of GCDCA detrimentally affects
hepatocytes.

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3.2.3. Autophagy in GDM regulation of ULK1 by miR-33b-3p, hence contributing to placental

The body undergoes a number of changes during pregnancy,
including a rise in hormonal and blood glucose levels to support fetal
growth. Increased hormone levels in pregnant women, such as cortisol,
progesterone, and other antagonistic insulin-like substances, may
induce insulin resistance, leading to reduced glucose uptake by cells and
consequently higher blood sugar levels [92]. Normally, islet β cells can
maintain blood glucose balance through autophagy, while hyperglyce­
mia can induce excessive autophagy of pancreatic β cells and worsen
insulin resistance [93]. By raising advanced glycation end products or
oxygen radical levels in cells, hyperglycemia promotes ROS and oxida­
tive stress. As a result, it induces excessive autophagy of trophoblasts,
impedes placental angiogenesis, and causes placental ischemia and
hypoxia [94]. At the same time, it was found in in vitro cell culture
experiments that hyperglycemia would induce excessive autophagy in
trophoblasts. Compared with cells cultured in a normal sugar environ­
ment, trophoblasts exposed to high glucose levels showed a significant
increase in the expression of the autophagy marker LC3 [94]. However,
another research has proved that hyperglycemia can increase
low-density lipoprotein transcytosis by suppressing autophagy in human
endothelial cells [95]. Bao Y et al. revealed several dysregulated circular
RNAs in GDM placenta that influenced the PI3k-Akt and insulin
signaling pathways. For example, increased circCDH2 may inhibit the
autophagy in GDM [96]. In summary, hyperglycemia can both over
activate and inhibit autophagy, and the effects on placental function
require deeper investigation.
3.2.4. Autophagy in other pregnancy related diseases
In addition, autophagy may be linked to other diseases, such as FGR
and RM. Deterioration of the endometrial environment is an important
trigger of RM. Aberrant crosstalk between amino acid metabolism and
autophagy may elevate autophagic activity, thus impairing the endo­
metrial microenvironment and inducing RM [97]. Cadmium triggers
BCL2 interacting protein 3-dependent mitophagy in placental tropho­
blasts and reduces maternal serum progesterone levels, resulting in FGR
[98]. Autophagy serves as a protective mechanism for trophoblast cells
against oxidative stress, while overactivity of autophagy may ultimately
compromise the function of trophoblasts, resulting in placental hypo­
perfusion, which in turn causes an insufficient supply of both nutrients
and oxygen in fetal development [99].

Fig. 4. Pyroptosis signaling pathway in pregnancy related diseases.In the canonical pathway, a range of external and internal stressors recruit effector proteins
(mainly ASC and NLRP3) to assemble inflammasomes, which in turn activate caspase-1. In the non-canonical pathway, LPS activates caspase-4, -5, and -11, which
cleave GSDMD into GSDMD-C and GSDMD-N. The latter oligomerizes and forms pores in plasma membranes, resulting in the influx of water and sodium ions and the
efflux of DAMPs, leading to membrane rupture. At the same time, caspase-1 proteolytically matures proIL-18 and proIL-1β into IL-18 and IL-1β, which spill
extracellularly and mediate the inflammatory response. Moreover, activated caspase-3 cleaves GSDME and promotes pore formation. Multiple stressors and mo­
lecular dysregulation during pregnancy can promote the formation of inflammasomes, induce placental inflammatory response and pyroptosis, and ultimately lead to
adverse pregnancy outcomes.(DAMPs, damage associated molecular patterns; PAMPs, pathogen-associated molecular patterns; dsDNA, double-stranded DNA; AIM2,
absent in melanoma 2; NLRC4, NLR family CARD domain containing 4; NINJ1, ninjurin 1; ZIKV, zika virus; FOXO3, forkhead box O3).

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X. Xie et al.
4. Pyroptosis
4.1. Mechanisms of pyroptosis
Pyroptosis is a recently discovered mode of programmed cell death
marked by its reliance on inflammatory cysteine asparaginases (mainly
caspase-1, -4, -5, and -11) and the release of numerous pro-inflammatory
molecules [100]. Pyroptosis related pathways are categorized into ca­
nonical and non-canonical pathways (Fig. 4).
The canonical pathway is mediated by inflammasome assembly with
gasdermin D (GSDMD) cleavage and the release of IL-1β and IL-18 [101,
102]. Upon the host’s resistance to microbial infection or other stressors,
the multimolecular complex inflammasomes are activated, promoting
an adaptive immune response. Inflammasome assembly begins with
cytoplasmic pattern recognition receptors (PRR), and the majority of
inflammasomes contain the caspase recruitment domain of the adapter
apoptosis-associated speck-like protein containing CARD (ASC), as well
as procaspase-1 [103–106]. In the inflammasome, activated caspase-1
cleaves GSDMD into GSDMD-CT and GSDMD-NT, and the latter perfo­
rates the cell membrane to create a non-selective pore, leading to cell
swelling and pyroptosis [107–109]. In addition, caspase-1 cleaves the
precursors of IL-1β and IL-18 into their active forms, which are released
in the extracellular space and induce an inflammatory response and
pyroptosis [110].
In the non-canonical pathway, cytoplasmic lipopolysaccharides
(LPS) activate caspase-4, -5, and -11, initiating pyroptosis via cleaving
GSDMD into GSDMD-NT, which aggregates and translocates to the cell
membrane to form a pore [111]. Cleavage of GSDMD causes the
exocytosis of K+, inducing the assembly of the NOD-like receptor fam­
ily, pyrin domain-containing protein 3 (NLRP3) inflammatory vesicle,
ultimately leading to pyroptosis [112].
Besides these two main pathways, specific stimuli can lead to
caspase-3 activation and induce the cleavage of gasdermin E (GSDME) to
GSDME-NT, which also participates in the formation of plasma mem­
brane pores, eventually resulting in pyroptosis [113]. However, recent
studies have shown that GSDMD-mediated pyroptosis can be hindered
by certain factors. Cleavage of GSDMD by caspase-3 and -7 at the Asp87
site leads to inactivation of GSDMD’s pyroptosis activity [114]. Addi­
tionally, the endosomal sorting complex required for the transport
mechanism eliminates the GSDMD pore at the plasma membrane,
thereby inhibiting GSDMD-mediated pyroptosis and restricting the
release of IL-1β [115]. Recently, it has been reported that activated
p-STAT3 promotes nuclear PD-L1 translocation under hypoxia. Nuclear
PD-L1 and p-STAT3 synergistically enhance GSDMC expression, and
activated caspase-8 can cleave GSDMC into GSDMC-NT, ultimately
leading to pyroptosis [116].
4.2. Pyroptosis in pregnancy-related diseases
4.2.1. Pyroptosis in PE
Pyroptosis has a widespread impact on obstetric disorders, particu­
larly PE. Compared to healthy pregnant women, pregnant women with
PE exhibit increased levels of NLRP3 inflammasome expression in both
blood cells and the placenta [117]. The secretion of multiple inflam­
matory mediators triggered by persistent inflammation in endothelial
cells leads to activation of NLRP3, which causes release of IL-1β and
IL-18 through the pores formed by the GSDMD, resulting in focal cell
death and then triggering PE [118,119]. In placental tissues from PE
patients and in hypoxia/reoxygenation-treated HTR8/Svneo cells,
heightened expressions of SET domain containing lysine methyl­
transferase 7 (SETD7) and HTRA1 propel pyroptosis and impair cell
migration and invasion [120]. Down-regulated HDAC2 in PE patients
accompanies elevated levels of FOXO3 and PERK, as well as IL-1β and
IL-18 expression, inhibiting cell proliferation, migration, and invasion,
ultimately leading to trophectodermal pyroptosis [121]. Moreover,
excessive ER stress induced by hypoxia in PE hyperactivates UPR, which
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Biomedicine & Pharmacotherapy 176 (2024) 116815
elevates thioredoxin-interacting protein and then activates the NLRP3
inflammasome, boosting the production of active caspase-1 [122]. In
addition, glycolysis in the trophoblast layer of PE patients is upregulated
but less efficient, resulting in attenuated ATP synthesis, potentially
associated with LPS-induced toll-like receptors 4 (TLR4)/NF-κB activa­
tion that disrupts the mitochondrial structure and function of tropho­
blasts and induces pyroptosis [123].
4.2.2. Pyroptosis in other pregnancy related diseases
Pyroptosis is implicated in placental implantation, formation, and
anti-infection; nonetheless, pyroptosis hyperactivation can be mutually
causal with obstetric complications [124]. Recent research has revealed
that maternal hypothyroidism activates classical inflammatory and
pyroptosis pathways at the maternal-fetal interface by triggering
oxidative stress and ER stress [125]. ZIKV has been shown to cause
placental pyroptosis through activating the actuator GSDME in vitro and
vivo, leading to adverse fetal outcomes in ZIKV-infected mice. In
mechanisms, the recognition of viral genomic RNA by retinoic
acid-inducible gene I induces the release of TNF-α, which activates
caspase-8 and caspase-3 and leads to the cleavage of GSDME, associated
with the creation of a dysplastic fetus [126]. Pregnant women with GDM
are frequently accompanied by hyperglycemia. It has been revealed that
exposure of TP53-induced glycolysis and apoptosis regulator-deficient
trophoblasts to high glucose induces the assembly of the NLRP3
inflammasome and leads to pyroptosis [127]. TP53-induced glycolysis
and apoptosis regulator deficiency is followed by overproduction and
release of ROS, along with poor placental decidualization and adverse
fetal outcomes [128]. Recurrent spontaneous abortion (RSA) is a com­
mon pregnancy complication that significantly impacts the physical and
mental health of pregnant women. Although the mechanisms behind
RSA remain unclear, the high mobility group box 1 molecule has been
found to be highly expressed at the maternal-fetal interface in patients
with unexplained RSA [129]. High expression of high mobility group
box 1 in RSA group is actively phagocytosed by macrophages, which
activates pyroptosis via the TLR2/TLR4/NF-kB pathway, leading to
inflammation and ultimately triggering RSA [130].
5. Necroptosis
5.1. Mechanisms of necroptosis
As a regulated form of necrotic cell death distinct from conventional
apoptosis signaling pathways, necroptosis is independent of caspase
activity and exhibits necrotic phenotypes, including organelle swelling
and cytolysis [131]. Necroptosis can be activated by the same triggers as
apoptosis and serves as a backup mechanism for apoptosis [132].
Necroptosis is initiated by various cytokines and PRRs. Key proteins
involved in executing necroptosis include receptor-interacting protein
kinase 1(RIPK1), RIPK3 and mixed lineage kinase domain-like proteins
(MLKL), which combine to form the necrosome [133]. Upon activation
of TNF signaling, RIP1 undergoes deubiquitylation by cylindromatosis
(CYLD) and interacts with RIPK3 in the absence of caspase-8 activity
[24]. In addition, TLR3 binding to dsDNA, TLR4 attaching to LPS, and
Z-conformation nucleic acid binding protein 1 (ZBP1) detecting DNA
viruses can all activate RIPK3 [134,135]. RIPK3 then phosphorylates
MLKL, prompting MLKL to oligomerize and transfer to the plasma
membrane. Consequently, there is an increase in plasma membrane
permeability, resulting in uncontrolled release of intracellular contents
and eventual cell death (Fig. 5) [136]. Besides, there exist other
signaling pathways that mediate necroptosis, and more details warrant
further investigation.
Necroptosis mediators have been linked to the pathophysiology of
autoimmune disorders, acute respiratory distress syndrome, myocardial
infarction, stroke, and other diseases. The modulatory effects of nec­
roptosis on the immune system and the underlying link between nec­
roptosis and several other forms of programmed cell death, as well as
X. Xie et al. Biomedicine & Pharmacotherapy 176 (2024) 116815

Fig. 5. Necroptosis signaling pathway in pregnancy related diseases.TNF-α binding to TNFR1 induces the formation of complex I. In conditions where c-FILP levels
are low and caspase-8 maintains normal activity, apoptosis is initiated. By contrast, when caspase-8 is inhibited, RIPK1 participates in the formation of complex IIb
under the deubiquitylation of CYLD and activates RIP3. Subsequently, RIP3 phosphorylates MLKL in the necrosome, causing MLKL oligomerization and translocation
to the plasma membrane, compromising the integrity of the membrane, and resulting in the influx of sodium ions and the efflux of DAMPs. Additionally, LPS, viruses,
and ER stress can exacerbate the detrimental effect of MLKL on the plasma membrane via different pathways. Several important components of necroptosis are
significantly elevated in models of pregnancy-related diseases, suggesting their crucial role in disease pathogenesis.(TRAF, tumor necrosis factor receptor-associated
factor; STAPA2, spermatogenesis-associated protein 2; TRIF, TIR domain-containing adaptor inducing interferon-β).

various inhibitors targeting the regulatory elements of the necroptotic
process, are currently under development [137,138].
5.2. Necroptosis in pregnancy related diseases
5.2.1. Necroptosis in PE
Current research suggests that the early placenta contains important
elements of necroptosis, with emerging data indicating a close associa­
tion between necroptosis and the onset of PE [139]. The formation of the
RIPK1-RIPK3 complex depends on the NAD-dependent deacetylase
SIRT2, which deacetylates and activates RIPK1 [140]. SIRT2 has been
found in various placental components, including the amnion epithe­
lium, decidual cells, cytotrophoblasts, and vascular endothelial cells
[141]. A large amount of SIRT2 in the placenta may trigger the creation
of the RIPK1-RIPK3 complex and send death signals, potentially trig­
gering necroptosis and shedding of trophoblast cells. Elevated levels of
these exfoliated aggregates of trophoblast cells have been found in the
circulatory system of PE patients, which can cause placental endothelial
dysfunction and induce PE [142]. In addition, Yu H et al. discovered that
the decrease in the expression of SIRT3 in the trophoblast of PE patients
led to increased expression of RIPK1, RIPK3, and p-MLKL, which
promotes necroptosis and inhibits trophoblast invasion and migration in
hypoxia [143]. Consequently, cell invasion stopping at a superficial
level impedes the formation of new blood vessels, causing placental
hypoxia and dysfunction. What’s more, inhibition of G protein-coupled
receptor kinase 2 in the PE placenta contributes to inadequate vascular
remodeling and enhanced trophoblast necroptosis with the activation of
RIPK1, RIPK3, and MLKL [144]. According to a recent study based on
necroptosis-related differentially expressed genes, necroptosis may
encourage the progression of PE through inducing immunological
infiltration and immune responses [145]. In summary, various func­
tional proteins and immune factors regulate necroptosis in the placenta,
thus causing placental dysfunction in different ways.
5.2.2. Necroptosis in other pregnancy related diseases
Necroptosis is implicated in other pregnancy related diseases such as
RM and FGR. According to animal experiments, deficiency of PR-SET7 in
the trophoblast inhibits endogenous retroviruses, which causes an
abnormal buildup of double-stranded RNA in the cytoplasm, giving rise
to inflammation, necroptosis, and ultimately miscarriage [146,147].
Currently, there are few studies on the relationship between necroptosis
and pregnancy related diseases, and more underlying mechanisms still

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X. Xie et al. Biomedicine & Pharmacotherapy 176 (2024) 116815

need to be further studied.
6. Ferroptosis
6.1. Mechanisms of ferroptosis
The term "ferroptosis" refers to a type of programmed cell death
brought on by perturbations of the intracellular microenvironment,
especially the accumulation of toxic lipid peroxidation, which depends
on ROS production and iron availability [148]. Morphological changes
of ferroptotic cells include a distinctive rounded shape before cell death,
a complete nucleus without condensation, and smaller mitochondria
with increased membrane density [149]. Ferroptosis may be brought on
by the buildup of glutamate, iron, and polyunsaturated fatty acids
(PUFAs) or by the depletion of glutathione (GSH) and nicotinamide
adenine dinucleotide phosphate (NADPH) [150]. Instead, iron chelators,
lipid peroxidation inhibitors, and a reduction in polyunsaturated fatty
acids can all inhibit ferroptosis [151].
The combination of iron-bound transferrin and transferrin receptor
(TFR) induces the import of Fe3+, which is subsequently reduced to
Fe2+ and transported into the cytosol via divalent metal transporter 1
(DMT1) [149]. However, this process intensifies with increased
expression of the transferrin receptor, leading to ferroptosis. Free Fe2+
serves as a catalyst for the generation of •OH and hydroxide ions from
H₂O₂, resulting in the peroxidation of PUFAs such as arachidonic acid
and adrenic acid [152]. Nevertheless, the exact cellular membranes
related to the lipid peroxidation in ferroptosis remain uncertain.
System Xc− , composed of SLC7A11 and SLC3A2, exchanges gluta­
mate for cystine in a 1:1 ratio in a normal state to enable the release of
glutamate into the extracellular environment and conversion of cystine
into cysteine, which is the primary limiting substrate for the synthesis of
glutathione [150]. As a reductant, glutathione peroxidase 4 (GPX4)
mediates the reduction of phospholipid hydroperoxides (PLOOHs)
[153]. GPX4 converts lipid hydroperoxides to lipid alcohols, thereby
avoiding the iron (Fe2+)-dependent generation of harmful lipid ROS.
Consequently, when GPX4 is inhibited, PLOOHs persist longer and
interact with both Fe2+ and Fe3+ to produce free radicals such as PLO•
and PLOO•, fueling the damaging peroxidation chain reaction (Fig. 6)
[154].
Apart from the cysteine-GSH-GPX4 axis, recent studies have unveiled
GPX4-independent mechanisms of ferroptosis, including the NAD(P)H-
ferroptosis suppressor protein 1-ubiquinone (NAD(P)H-FSP1-CoQ10)

Fig. 6. Ferroptosis signaling pathway in pregnancy related diseases.The ferroptosis signaling pathway is characterized by iron overload, lipid peroxidation, and
impaired GPX4 activity. Upon transportation into cells by TFR1 and DMT1 and subsequent reduction by STEAP3, excess iron participates in the production of ROS,
thereby promoting lipid peroxidation. Dysfunctional ferritin light chain, as observed in PE, aggravate the buildup of intracellular iron and oxidative stress. In
pregnancy related diseases, dysfunction of system Xc− and depletion of GSH lead to the inhibition of GPX4 activity, thus failing to counteract lipid peroxidation,
resulting in structural and functional impairment of trophoblast cells. Cellular metabolic disorders caused by excess sugar and mitochondrial stress also boost the
process of lipid peroxidation.(STEAP3, six-transmembrane epithelial antigen of prostate 3; FTL, ferritin light chain; GLUT, glucose transporter; Glu, glutamicacid).

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X. Xie et al.
pathway [155]. These findings highlight the complexity of ferroptosis
regulation and suggest that more ferroptosis signaling pathways with
distinct biological functions are awaiting exploration.
6.2. Ferroptosis in pregnancy related diseases
6.2.1. Ferroptosis in PE
Based on the information provided, it’s evident that iron overload
and ROS are closely associated with ferroptosis. A cross-sectional study
revealed significantly elevated serum levels of iron, ferritin, transferrin
saturation, hepcidin, and lipid peroxidation byproducts like malon­
dialdehyde in PE patients [156]. Reduced circulation selenium, GPX4
activity, and lower placental GSH levels in PE suggest that insufficient
antioxidant defenses may cause oxidative stress and the development of
PE [157,158]. The sudden increase in oxygen and iron resulting from
hypoxia/reperfusion events between the 8th and 10th weeks of preg­
nancy causes membrane lipid peroxidation and overactivated ferropto­
sis at the maternal-fetal interface. This phenomenon contributes to
shallow endovascular EVCT infiltration and defective uterine spiral ar­
tery remodeling, which are pathologic characteristics of PE [159].
Recent studies have shown that FTL increases intracellular iron accu­
mulation, promoting oxidative stress-induced ferroptosis and defective
uterine spiral artery remodeling [160]. Furthermore, the promotion of
ferroptosis and oxidative stress in PE may be mediated by an interaction
between elevated expression of the transmembrane channel protein
pannexin 1 and activated TLR4 [161]. Evidence suggests that
miR-30b-5p overexpression in PE is essential for ferroptosis. Concretely,
the upregulation of miR-30b-5p leads to the downregulation of SLC7A11
and paired box 3 expression, further causing decreased levels of ferro­
portin 1 and intracellular GSH levels, which in turn leads to the buildup
of free iron within cells. The decreased glutathione and iron accumu­
lation then trigger ferroptosis, ultimately compromising the function of
the trophoblast [162].
6.2.2. Ferroptosis in GDM
The correlation between diabetes and iron overload significantly
influences disease progression. Excessive iron levels damage the
pancreatic β-cells through oxidative stress, leading to insulin resistance
and elevating the susceptibility to diabetes; meanwhile, diabetes pro­
motes iron accumulation, which raises ferritin levels [163,164]. In
GDM, hyperglycemia circumstances stimulate the upregulation of
SIRT3, which causes trophoblast ferroptosis by enhancing the
AMPK-mTOR pathway and suppressing cellular GPX4 levels [165].
Abnormal lipid metabolism frequently coexists with aberrant glucose
metabolism in patients with diabetes mellitus [166]. High levels of free
fatty acids in GDM patients hinder insulin-induced glucose uptake,
which further strengthens insulin resistance and increases the risk of
GDM [167]. Adiponectin, an insulin sensitizer that decreases in GDM
patients, weakens the effects of fatty acid oxidation/peroxide
imbalance-mediated ferroptosis and ameliorates placental damage
caused by hyperlipidemia and hyperglycemia [164]. Additionally,
recent research demonstrates that overexpressed CircHIPK3 in GDM
patients promotes ferroptosis through miR-1278/DNMT1 to control
GPX4 DNA methylation [168].
6.2.3. Ferroptosis in other pregnancy related diseases
The role of ferroptosis in other pregnancy related diseases also re­
ceives significant interest. High hemoglobin concentrations caused by
excess iron intake or high iron levels during pregnancy may increase
blood viscosity and damage placental blood flow, thus increasing the
risk of preterm birth [169]. Uterine contractions, a defining feature of
spontaneous preterm birth, are associated with placental hypoxia/r­
eoxygenation and an increase in lipid mediators and related enzymes,
both of which are risk factors for ferroptosis [170]. Furthermore,
Decreased GPX4 expression in placental trophoblast cells in spontaneous
abortion patients suggests a potential role of ferroptosis in first-trimester
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Biomedicine & Pharmacotherapy 176 (2024) 116815
fetal demise [171]. Both low serum iron levels and decidual local iron
deposition have been observed in patients with recurrent pregnancy loss
(RPL). Iron death inhibitors, cysteine, and GSH supplementation have
shown promise in lowering decidual stromal cell ferroptosis and
reversing embryonic loss in spontaneous abortion models [172].
Therefore, ferroptosis in decidual stromal cells may be involved in the
pathogenesis of RPL. According to the research by Fang et al., GPX4 and
the expression of epidermal growth factor receptor, which has been
demonstrated to participate in the regulation of ferroptosis, are both
elevated in the ICP group, suggesting the relationship between ferrop­
tosis and ICP [173].
7. Cell death-based therapeutic implications
Cell death is essential for morphogenesis and homeostasis mainte­
nance, as it facilitates the removal of contaminated cells to prevent
pathogens from proliferating. Impaired or over-activated cell death
pathways contribute to the occurrence of pregnancy related diseases.
Therefore, therapeutics for treating related diseases by correcting cell
death imbalances are burgeoning (Table 1).
Evidence indicates that moderate maternal nutritional intake during
pregnancy can prevent illnesses by inhibiting apoptosis. Hyper­
homocysteinemia, characterized by increased oxidative stress, can
trigger apoptosis. However, early supplementation with folate, vitamin
B12, and long-chain polyunsaturated fatty acids can prevent the devel­
opment of hyperhomocysteinemia, thereby reducing the risk of pre­
eclampsia [38]. According to research, saturated free fatty acids
promote placental trophoblast apoptosis through activating caspase-3
and -7, which can be counteracted by monounsaturated fatty acids,
indicating the therapeutic potential of monounsaturated fatty acids
[174]. Studies have also found that short-chain fatty acids promote
macrophage autophagy, thus inhibiting macrophage inflammation and
alleviating PE [175]. Moreover, an in vitro study has found that vitamin
D can increase the viability of HUVEC, which suggests that vitamin D
may be propitious for decreasing inflammation and cell death in the
placenta of PE patients [176].
Some hormones and medications are believed to alleviate pregnancy
related diseases by restoring the balance of cell death. Progesterone
stimulates trophoblast invasion and suppresses apoptosis, thereby alle­
viating PE-like symptoms caused by SIRT1 deficiency [177]. Melatonin
has been shown in studies to decrease HTRA1 transcription via the
miR-520c-3p/SETD7 axis, enhancing invasion and migration of
trophoblast and inhibiting trophoblasts pyroptosis in PE [120]. Several
natural compounds, such as atractylenolide and puerarin, attenuate
apoptosis and oxidative stress in PE by activating or inhibiting different
signaling pathways [178,179]. Ferulic acid, derived from plants, may be
capable of treating PE through preventing cell damage and apoptosis
induced by oxidative stress and inflammation [32]. According to recent
reports, autophagy maintenance may be a possible treatment target for
PE. Cyclosporine A, an immunosuppressant, may boost EVT prolifera­
tion, migration, and invasion by triggering autophagy while also pro­
tecting trophoblasts from oxidative stress [180]. However, excessive
autophagy caused by long-term hypoxia may induce cell death and
impair placental function. Esomeprazole relieves PE-like symptoms by
blocking excessive placental autophagy through the SIRT1/AMPKα-m­
TOR pathway, preventing the release of toxic substances detrimental to
the maternal vasculature [84]. Excess iron and the buildup of fatal lipid
molecules from lipid peroxidation play an indispensable part in fer­
roptosis. Iron chelators (e.g., deferiprone, deferoxamine), small lipo­
philic antioxidants (e.g., ferritetin, liplastin), and GSH and cystine (the
raw material for GSH production) can all contribute to reducing the risk
of ferroptosis-induced illnesses and improving pregnancy outcomes
[149,172].
Furthermore, a range of signaling pathways, protein molecules,
genes, and RNAs involved in cell death represent potential targets for the
therapy of pregnancy related diseases. IL-15, an inflammatory factor
X. Xie et al. Biomedicine & Pharmacotherapy 176 (2024) 116815

Table 1
Cell death-based therapeutic implications for pregnancy related diseases.
Cell death Drugs or compounds Mechanisms Diseases Refs

Apoptosis folate, vitamin B12, and long chain Preventing hyperhomocysteinemia PE [38]
polyunsaturated fatty acids
monounsaturated fatty acids Inhibiting activation of caspase-3 and -7 PE, GDM, IUGR and maternal [174]
inflammation
vitamin D Decreasing inflammation and cell death PE [176]
progesterone Stimulating trophoblast invasion and suppresses apoptosis PE [177]
atractylenolide Inhibiting apoptosis and oxidative stress by activating MAPK/ PE [178]
ERK signalling
puerarin Alleviating inflammation and apoptosis PE [179]
ferulic acid Preventing cell damage and apoptosis PE [32]
CLEC4GP1 Inhibits IL-15 mRNA stability PE [181]
ERp29 suppression Inhibiting phosphorylation and kinase activity of p38, thus ICP [183]
reversing the harmful effects of taurocholic acid
acetylcholine Inhibiting activation of p38 MAPK and NF-κB PE [184]
Autophagy short-chain fatty acids Promoting macrophage autophagy PE [175]
cyclosporine A Boosting EVT proliferation, migration, and invasion by PE [180]
triggering autophagy
esomeprazole Blocking excessive placental autophagy through the SIRT1/ PE [84]
AMPKα-mTOR pathway
Pyroptosis melatonin Decreasing HTRA1 transcription via the miR-520c-3p/SETD7 PE [120]
axis
metformin Blocking TLR4/NF-κB signaling PE [123]
kisspeptin-10 Prevents the activation of the inflammasome-NLRP3 and the gestational diseases that involve [125]
placental pyroptosis inflammasome activation and pyroptosis
Ferroptosis deferiprone, deferoxamine, ferritetin, Inhibiting ferroptosis PE, GDM, RPL and spontaneous preterm [149,
liplastin, GSH and cystine birth 172]

found to be upregulated in PE placenta, exerts detrimental effects. A
pseudogene named C-type lectin domain family 4 member G pseudo­
gene 1 inhibits IL-15 mRNA stability, which in turn inhibits trophoblast
cell apoptosis and promotes invasion [181]. p38 MAPKs,
serine/threonine-specific protein kinases, allow cells to react to stimuli
and influence cell proliferation, apoptosis, autophagy, and tumor
growth [182]. According to research, ERp29 suppression could reduce
apoptosis in ICP through inhibiting the phosphorylation and kinase ac­
tivity of p38, therefore reversing the harmful effects of taurocholic acid
[183]. Acetylcholine may weaken hypoxia-induced oxidative stress and
apoptosis via inhibiting activation of p38 MAPK and NF-κB, suggesting
that increased vagal activity may be beneficial for treating PE [184]. The
activation of NLRP3 inflammasomes serves as a vital link in pyroptosis,
which occurs in pregnancy illnesses such as PE and GDM. Thus, NLRP3
inhibitors may be an alternative for treatment [119]. For example,
through blocking TLR4/NF-κB signaling in a PE trophoblast model,
metformin inhibits the pyroptosis triggered by the NLRP3 inflamma­
some [123]. A recent study has found that kisspeptin-10 hinders the
activation of the NLRP3 inflammasome and placental pyroptosis
brought on by maternal hypothyroidism, implying that kisspeptin ana­
logues may hold promise for managing pregnancy diseases associated
with pyroptosis [125].
More regulators and effectors of cell death pathways open up new
avenues for therapeutic intervention and are expected to be applied in
clinical practice, contingent on further research on the underlying
mechanisms of pregnancy related diseases.
intolerance, which increases the risk of diabetes and other near- and
long-term complications in pregnant women and fetuses. Meanwhile,
pregnancy related diseases can exacerbate the dysregulation of cell
death, creating a vicious cycle that ultimately results in adverse preg­
nancy outcomes. Therefore, studies in mounting numbers have put great
emphasis on the role of cell death in pregnancy related diseases, espe­
cially the newly discovered pyroptosis, ferroptosis, and necroptosis, in
order to provide potential therapeutic strategies targeting relevant
signaling pathways.
However, the mechanisms of cell death have yet to be fully eluci­
dated, and the signaling pathways involved in the development of
pregnancy related diseases remain unclear. Among them, there are
fewer studies on the relationship between necroptosis and pregnancy
related disorders, resulting in a lack of understanding in this area. In the
meantime, most of the current treatment strategies for pregnancy
related diseases based on cell death are derived from in vitro experi­
ments and have not yet entered clinical trials. Consequently, it is still
unknown whether these strategies can be effectively applied in clinical
practice. We hope that deeper studies in the future will reveal the po­
tential mechanisms linking cell death and pregnancy related diseases
and provide valuable insights for the development of meaningful ther­
apeutic strategies.
Ethics approval and consent to participate
Not applicable.

8. Conclusions and future perspectives Consent for publication

Cell death is indispensable for the regular growth of the organism as Not applicable.
well as maternal health and fetal development throughout pregnancy, as
it allows for the removal of extra or damaged cells produced by high
CRediT authorship contribution statement
proliferation along with the optimal formation and maturation of tissues
and organs through the elimination of undesired cells. Nevertheless,
Yan Zhang, Ru Zhu and Yun Zhang conceived this project. Xiaowen
abnormalities in trophoblast cell death lead to a homeostatic imbalance
Xie, Jiayu Liu, Jingyi Gao and Chenwei Shang wrote the original draft.
of local placental tissue, disrupting trophoblast cell migration and in­
Xiaowen Xie and Chenwei Shang designed the figures. Chenwei Shang,
vasion and spiral artery remodeling, consequently resulting in preg­
Ying Jiang, Lingyan Chen, Zhiwen Qian, Lu Liu and Danping Wu
nancy related diseases. Excessive cell death of maternal pancreatic β
collected the data and performed the analysis. Yan Zhang and Xiaowen
cells leads to impaired pancreatic β cell function and maternal glucose
Xie revised the manuscript. Yan Zhang got financial support. All authors

12
X. Xie et al.
reviewed and approved the final manuscript.
Funding
The study was partially supported by Major project of Wuxi Science
and Technology Bureau (N20201006), Wuxi Double-Hundred Talent
Fund Project (BJ2023075), Wuxi Health Commission Precision Medi­
cine Project (J202106), Jiangsu Provincial Maternal and Child Health
Research Project (F202034) and Jiangsu Provincial Six Talent Peaks
Project (No. YY-124).
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Data availability
No data was used for the research described in the article.
Acknowledgements
The figures in this manuscript were created using BioRender, a
valuable tool for scientific illustrations. We would like to thank Bio­
Render for granting us permission to use their images in this publication.
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