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The Role of Ferroptosis in Placental-Related Diseases

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Abstract

Ferroptosis is a recently identified form of programmed cell death which is different from apoptosis, pyroptosis, necrosis, and autophagy. It is uniquely defined by redox-active iron-dependent hydroxy-peroxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids and a loss of lipid peroxidation repair capacity. Ferroptosis has recently been implicated in multiple human diseases, such as tumors, ischemia–reperfusion injury, acute kidney injury, neurological diseases, and asthma among others. Intriguingly, ferroptosis is associated with placental physiology and trophoblast injury. Circumstances such as accumulation of lipid reactive oxygen species (ROS) due to hypoxia-reperfusion and anoxia-reoxygenation of trophoblast during placental development, the abundance of trophoblastic iron and PUFA, physiological uterine contractions, or pathological placental bed perfusion, cause placental trophoblasts’ susceptibility to ferroptosis. Ferroptosis of trophoblast can cause placental dysfunction, which may be involved in the occurrence and development of placenta-related diseases such as gestational diabetes mellitus, preeclampsia, fetal growth restriction, preterm birth, and abortion. The regulatory mechanisms of trophoblastic ferroptosis still need to be explored further. Here, we summarize the latest progress in trophoblastic ferroptosis research on placental-related diseases, provide references for further understanding of its pathogenesis, and propose new strategies for the prevention and treatment of placental-related diseases.

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Data Availability

The datasets generated and or analysed during the current study are available online. No consent was required as the study used data that has already been published online.

Abbreviations

ACSL4 :

Acyl-CoA synthetase long-chain family member 4

AMPK:

Activated protein kinase

BAP1 :

BRCA1-associated protein 1

BECN1 :

Beclin 1

BM :

Basal membrane

BMI :

Body mass index

CTB :

Cytotrophoblasts

CoQ10 :

Coenzyme Q10

DMT1 :

Divalent metal transporter 1

Fe 2+ :

Ferrous iron

Fe 3+ :

Ferric iron

FGR :

Fetal growth restriction

FPN1 :

Ferroportin 1

FSP1 :

Ferroptosis suppressor protein 1

GDM :

Gestational diabetes mellitus

GPX4 :

Glutathione peroxidase 4

GPXs :

Glutathione peroxidases

GSH :

Glutathione

HbA1c :

Hemoglobin A1c

H2O2 :

Hydrogen peroxide

IREB2 :

Iron response element binding protein 2

IRP1/2 :

Iron regulatory protein 1/2

LIP :

Labile iron pool

LOXs :

Lipoxygenases

LPCAT3 :

Lysophosphatidylcholine acyltransferase 3

MVM :

Microvillous plasma membrane

NAD(P) :

Nicotinamide adenine dinucleotide phosphate

OGTT :

Oral glucose tolerance test

PCBP2 :

Poly(rC)-binding protein 2

PCD :

Programmed cell death

PCOS :

Polycystic ovary syndrome

PLA2G6 :

Phospholipase A2 group VI

PE :

Preeclampsia

PLOOHs :

Phospholipid hydroperoxides

PUFAs :

Polyunsaturated fatty acids

PUFA-PLs :

PUFA-containing phospholipids

ROS :

Reactive oxygen species

RSL3 :

RAS-selective lethal 3

SIRT3 :

Sirtuin 3

SLC7A11 :

Solute carrier family 7 member 11

SLC3A2 :

Solute carrier family 3 member 2

STB :

Syncytiotrophoblast

STEAP3/4 :

Six-transmembrane epithelial antigen of the prostate 3/4

TB :

Trophoblasts

Tf :

Transferrin

TFR1 :

Transferrin receptor 1

VDACs :

Voltage-dependent anion channels

WHO :

World Health Organization

ZIP 8/14 :

Zinc-iron regulatory protein family 8/14

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Southeast University Affiliated Zhongda Hospital, Nanjing, China

    Xiao Shen, Tianyi Yu & Hong Yu

  2. Medical School of Southeast University, Nanjing, China

    Nathan Obore, Yixiao Wang & Hong Yu

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  1. Xiao Shen
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  4. Tianyi Yu
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  5. Hong Yu
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Shen, X., Obore, N., Wang, Y. et al. The Role of Ferroptosis in Placental-Related Diseases. Reprod. Sci. 30, 2079–2086 (2023). https://doi.org/10.1007/s43032-023-01193-0

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