Insights into the pathogenesis of gestational and hepatic diseases: the impact of ferroptosis

Abstract

Ferroptosis, a distinct form of non-apoptotic cell death characterized by iron dependency and lipid peroxidation, is increasingly linked to various pathological conditions in pregnancy and liver diseases. It plays a critical role throughout pregnancy, influencing processes such as embryogenesis, implantation, and the maintenance of gestation. A growing body of evidence indicates that disruptions in these processes can precipitate pregnancy-related disorders, including pre-eclampsia (PE), gestational diabetes mellitus (GDM), and intrahepatic cholestasis of pregnancy (ICP). Notably, while ICP is primarily associated with elevated maternal serum bile acid levels, its precise etiology remains elusive. Oxidative stress induced by bile acid accumulation is believed to be a significant factor in ICP pathogenesis. Similarly, the liver's susceptibility to oxidative damage underscores the importance of lipid metabolism dysregulation and impaired iron homeostasis in the progression of liver diseases such as alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), cholestatic liver injury, autoimmune hepatitis (AIH), acute liver injury, viral hepatitis, liver fibrosis, and hepatocellular carcinoma (HCC). This review discusses the shared signaling mechanisms of ferroptosis in gestational and hepatic diseases, and explores recent advances in understanding the mechanisms of ferroptosis and its potential role in the pathogenesis of gestational and hepatic disorders, with the aim of identifying viable therapeutic targets.

Keywords: ferroptosis; liver diseases; pathogenesis; placenta; pregnancy.

FIGURE 1

Physiological cellular iron transport and regulation of ferroptosis. This figure illustrates the pathways involved in cellular iron transport and the regulatory mechanisms of ferroptosis. Iron is primarily transported as transferrin-bound iron (TBI). Plasma-derived transferrin (TF) binds to transferrin receptor 1 (TFR1) on the cell membrane, leading to receptor-mediated endocytosis of the TF-TFR1 complex. Within the acidified endosome, iron is released from TF after reduction by six-transmembrane epithelial antigen of the prostate 3 (Steap3), then transported to the cytoplasm via divalent metal transporter 1 (DMT1). Intracellular iron is either sequestered by ferritin or mobilized where needed. Excess iron, forming non-transferrin-bound iron (NTBI) in overloaded conditions, is managed by ZIP14 (SLC39A14) and ZIP8 (SLC39A8) at the plasma membrane. Ferroptosis regulation is broadly categorized into three pathways (Dixon et al., 2012). The glutathione/glutathione peroxidase 4 (GSH/GPX4) pathway, including the inhibition of system Xc⁻, the glutamine pathway, and the p53 regulatory axis (Zhang et al., 2023); Iron metabolism regulation, involving pathways such as the autophagy-related gene 5/7 - nuclear receptor coactivator 4 (ATG5/7-NCOA4) pathway, and iron regulatory element binding protein 2 (IREB2) related to ferritin metabolism, with increased of intracellular Fe²⁺ initiating the Fenton reaction (Zheng and Conrad, 2020); Lipid metabolism-related pathways, where long-chain acyl-CoA synthetase 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) paly roles in lipid regulation and ferroptosis. Additionally, Erastin induces ferroptosis by acting on mitochondria.

FIGURE 2

Ferroptosis-suppressing pathways. This figure depicts GPX4, ferroptosis suppressor protein 1 (FSP1), dihydroorotate dehydrogenase (DHODH), and GTP cyclohydrolase-1 (GCH1) suppress ferroptosis at different subcellular compartments. FSP1 is located at the plasma membrane where it functions as an oxidoreductase that reduces coenzyme Q10 (CoQ), suppressing lipid peroxidation. It prevents lipid peroxidation and associated ferroptosis via the reduction of ubiquinol/α-tocopherol on the level of lipid radicals unlike GPX4/GSH. FSP1 can also promote the endosomal sorting complex required for transport (ESCRT)-III to enhance the repair of cell membranes in a CoQ10-independent manner. FSP1-CoQ10-NAD(P)H axis can be activated through nuclear factor erythroid 2 related factor 2 (Nrf2) to inhibit ferroptosis. Synthesis of tetrahydrobiopterin/dihydrobiopterin (BH4/BH2) by GCH1-expressing cells caused lipid remodeling, suppressing ferroptosis by selectively preventing depletion of phospholipids.

FIGURE 3

Ferroptosis in early gestation. Before 8–10 weeks, spiral arteries are completely blocked by endothelial cells and clots, creating hypoxia and hypoglycemia in the embryo. Until the end of the first trimester (10–12 weeks), the spiral arteries open and a sudden increase in oxygen and iron can significantly accumulate ROS, oxidative stress, and tissue damage, inducing ferroptosis which contributes to remodeling the spiral arteries. Normally, villi are covered with villous cytotrophoblast and syncytiotrophoblast, containing fetal vessels covered with villous endothelium. Extravillous trophoblast (EVT) invasion causes spiral artery remodeling thereby creating low-resistant perfusion. Under ischemic conditions, the villous trophoblast becomes discontinuous. Increased fibrin and syncytial knotting deposit on the villous surface. Spiral arteries are inappropriately remodeled due to impaired EVT invasion and ischemia exposes villous tissue to increased oxidative stress. Factors such as iron status, antioxidants, environmental exposure, and ferroptosis-related genes can influence the process. However, the persistence of ferroptosis may cause pathological effects such as shallow trophoblast invasion and narrowing of the vascular lumen.