Preeclampsia is defined as the early event of hypertensive pregnancy with systolic blood pressure ≥140 mmHg and diastolic blood pressure ≥90 mmHg [1,2]. Preeclampsia is characterized by hypertension, a high level of protein in the urine, increased liver enzymes, vision alterations, nausea, vomiting, headaches, and pain. It is a critical factor contributing to morbidity and mortality during pregnancy [3]. Preeclampsia includes two subtypes: early-onset and late-onset preeclampsia. Both subtypes involve placental syncytiotrophoblast stress [4]. Importantly, early-onset preeclampsia is associated with inadequate spiral artery remodeling. Inadequate invasion of trophoblasts contributes to the early onset of preeclampsia due to their role in spiral artery remodeling. Under normal conditions, trophoblasts migrate to the uterine spiral artery to infiltrate it, replacing endothelial cells and inducing the death of smooth muscle cells. This process leads to vascular remodeling and promotes material transfer between the mother and the fetus [5]. However, inadequate trophoblast invasion may lead to abnormal vascular remodeling and the development or maintenance of the muscle elastic phenotype and perfusion abnormalities. This, in turn, promotes ischemia and chronic inflammation and induces preeclampsia [[6], [7], [8]]. Thus, impaired trophoblast migration and invasion serve as important factors in the pathogenesis of early-onset preeclampsia.

Poor trophoblast migration and invasion can lead to uteroplacental ischemia, which in turn causes hypoxia in the placenta. Hypoxia can result in trophoblast cell death. Cell death is believed to be the result of one of two distinct processes: programmed cell death and uncontrolled cell death. Currently, the most intensively investigated forms of programmed cell death include apoptosis, necroptosis, pyroptosis, ferroptosis, PANoptosis, and autophagy [9]. Ferroptosis is a newly discovered form of programmed cell death that occurs as a result of lipid peroxidation, which is triggered by the iron-dependent production of oxygen radicals [10]. It has been found to affect the migration and invasion of trophoblasts during early-onset preeclampsia. Approximately 18% of patients with preeclampsia exhibit high levels of transferrin saturation, suggesting iron overload in preeclampsia. Trophoblasts are susceptible to ferroptosis due to iron overload [11]. Recent studies on ferroptosis in preeclampsia have revealed a correlation between ferroptosis in trophoblasts and the development of a preeclampsia-like phenotype. A study reported that the absence of ferritin light chain causes a decrease in ferroptosis, leading to spiral artery remodeling disorders and hypertensive-like symptoms in pregnant rats [12]. They further determined that ferroptosis contributed to impaired spiral arterial remodeling by modulating trophoblast migration and invasion. Yang et al. suggested that ferroptosis could promote a preeclampsia-like phenotype in pregnant rats through the activation of trophoblast migration and invasion by Elabela, a small-molecule polypeptide [13]. Ferroptosis inhibitors can enhance trophoblast invasion into the spiral artery in both in vitro and in vivo models of preeclampsia [14]. Given the role of ferroptosis in trophoblasts, we conclude that inhibiting ferroptosis may play a crucial role in enhancing the migration and invasion of cells during preeclampsia.

ACSL4, which stands for acyl-CoA synthetase long-chain family member 4, has the ability to determine a cell's sensitivity to ferroptosis [15]. A decrease in ACSL4 can repress the biosynthesis of polyunsaturated fatty acid-containing lipids to prevent lipid peroxidation, suggesting that its plays a core role in ferroptosis [16]. ACSL4 is upregulated in the hypoxia-induced trophoblast model of preeclampsia [17], indicating its potential role in the process of ferroptosis-mediated preeclampsia. In this study, we investigated whether ACSL4 mediates ferroptosis to modulate trophoblast migration and invasion during preeclampsia. In addition to understanding the role of ACSL4 upregulation in trophoblast migration and invasion, it is also worth investigating the cause of ACSL4 upregulation. N6-methyladenosine (m6A) modification may enhance the expression of ACSL4 in trophoblasts. m6A is the most common RNA modification at the epigenetic level. Disease etiology involves the abnormal expression of various genes due to m6A modification [18]. Compared to healthy pregnant women, patients with preeclampsia showed an increase in m6A modification along with the overexpression of m6A genes [19]. This suggests that m6A modification is a significant event in the pathogenesis of preeclampsia. Using the SRAMP database (http://www.cuilab.cn/sramp), we identified highly reliable m6A sites within ACSL4 mRNA. This suggests that ACSL4 expression is influenced by m6A modification.

The m6A modification is dynamic and reversible, which is regulated by m6A “writer” proteins such as methyltransferases like 3/14 (METTL3/14) and Wilms tumor 1 associated protein (WTAP), and “eraser” protein Fat-mass and obesity-associated protein (FTO) and Alkylation repair homolog protein 5 (ALKBH5) [20]. Based on previous studies, METTL3 was found highly expressed in the placentas of patients with preeclampsia, and the dysregulation of METTL3 was considerable prominent [21,22]. METTL3 is the key enzyme responsible for catalyzing m6A methylation of specific transcripts [18]. Thus, the m6A modification of ACSL4 may be closely associated with METTL3 methyltransferase activity. This intriguing finding also raises a novel hypothesis that high levels of METTL3 expression can enhance ACSL4 expression in trophoblasts by catalyzing ACSL4 mRNA m6A modification. We speculate that the METTL3/ACSL4 axis has the potential to regulate ferroptosis in preeclampsia.

Collectively, these data support the new hypothesis that METTL3 catalyzes the N6-adenine methylation of ACSL4 mRNA to upregulate ACSL4 expression, which promotes ACSL4-mediated ferroptosis in trophoblasts during preeclampsia.