Ferroptosis and Its Emerging Role in Pre-Eclampsia

Abstract

Iron is essential for cell survival, and iron deficiency is a known risk factor for many reproductive diseases. Paradoxically, such disorders are also more common in cases of iron overload. Here, we evaluated the role of ferroptosis in women’s health, particularly focusing on pre-eclampsia (PE). PE is a multisystem disorder and is one of the leading causes of maternal and perinatal morbidity and mortality, especially when the condition is of early onset. Nevertheless, the exact etiological mechanism of PE remains unclear. Interestingly, ferroptosis, as a regulated iron-dependent cell death pathway, involves a lethal accumulation of lipid peroxides and shares some characteristics with PE pathophysiology. In this review, we comprehensively reviewed and summarized recent studies investigating the molecular mechanisms involved in the regulation and execution of ferroptosis, as well as ferroptosis mechanisms in the pathology of PE. We propose that ferroptosis not only plays an important role in PE, but may also become a novel therapeutic target for PE.

Regulatory mechanism and research progress of ferroptosis in obstetrical and gynecological diseases

“…Enriched PUFA, especially AA, has been reported in the trophoblasts of PE patients (Brown et al, 2016). Additionally, metabolomic analysis has revealed the presence of a significantly higher mitochondrial level of PUFA among PE patients, further validating the accumulation of PUFA (Chen et al, 2022). Moreover, the overexpression of several genes involved in disrupted lipid metabolism has been identified, including LPCAT3, ACSL4, which are two key gene products for membrane localization of PUFA to form PUFA-PL (Dixon et al, 2015;Ou et al, 2016;Kagan et al, 2017).…”

“…Furthermore, single-cell sequencing of placental trophoblasts, endothelial cells and mesenchymal fibroblasts showed the overexpression of LOX-5, LOX-15 and spermidine/spermine N1-acetyltransferase 1 (Sat1), which are key enzymes to trigger membrane lipid peroxidation (Dixon et al, 2015;Ou et al, 2016;Kagan et al, 2017). As such, MDA was also reported to be notably upregulated in gestational women who undergo PE in several investigations (Siddiqui et al, 2013;Yang et al, 2020;Chen et al, 2022). Collectively, the level of membrane-bound lipid peroxidation is significantly upregulated and OS level is escalated in trophoblasts under PE conditions.…”

“…This indicates that the fast and turbulent flow is possible to induce vascular lesions with the formation of foam cells and inflammatory response ( Staff et al, 2022 ). However, the mechanism underlying the formation of foam cells is still unclear, several studies suggest that this might be involved in ferroptosis-associated lipid peroxidation in trophoblasts due to the presence of lipid-enriched foam cells ( Alahari et al, 2018 ; Chen et al, 2022 ). Taken together, the intimate relationship is present in ferroptosis, inflammation and altered hemodynamics.…”

“…Among these obstetrical and gynecological conditions, settings associated with ferroptosis were found to be closely linked to preeclampsia (PE), endometriosis (EMs) and polycystic ovary syndrome (PCOS). Recently, more evidence has suggested the pathogenesis of PE is related to ferroptosis of trophoblasts, which might cause inflammatory responses, hypoxia-reperfusion injury, shallow invasion of trophoblasts and suboptimal spiral artery remodeling ( Orlov et al, 2016 ; Ng et al, 2019 ; Chen et al, 2022 ). It is considered that ferroptosis is inhibited at the ectopic lesion in EMs, which allows the endometrial cells to survive and grow in the iron overload and excessive OS condition ( Ng et al, 2020 ).…”

Role of ferroptosis in pregnancy related diseases and its therapeutic potential

“…4.1.1 Lipid peroxidation and pre-eclampsia PE plays a leading role in maternal morbidity and mortality (Leitao et al, 2022). Ferroptosis has been related to the pathogenesis of PE (Chen et al, 2022). There are mounting evidence suggesting lipid peroxidation, is a major contributor for the damage of PE.…”