Vitamin D may alleviate pre‐eclampsia by modulating the ferroptosis signalling pathway: A hypothesis based on recent literature

Abstract Ferroptosis is a novel form of regulated cell death typically characterized by non‐apoptotic, iron‐dependent, and reactive accumulation of oxygen species. Recent studies have found that ferroptosis plays an important role in the pathophysiology of pre‐eclampsia (PE). In order to find potential therapeutic targets for ferroptosis intervention and better prevent the occurrence and progression of PE, the signalling pathways that regulate ferroptosis need to be identified. In this article, we review the role of vitamin D in PE and the role of ferroptosis in PE. Based on recent literature, we propose the scientific hypothesis that vitamin D can alleviate preeclampsia by modulating the ferroptosis signalling pathway. The aim of this review is to understand the regulatory pathways of ferroptosis in PE and to identify potential therapeutic targets.


| INTRODUC TI ON
Pre-eclampsia (PE) is a major complication of pregnancy and is a significant burden to maternal and foetal health. A registry-based nationwide controlled cohort study found that PE significant elevated cardiovascular disease (CVD) risks of Finnish women. 1 A meta-analysis involving 39 million women from 40 countries showed that the overall estimates are 4.6% of all deliveries for preeclampsia. 2 PE is difficult to define because it is a syndrome characterized by many clinical manifestations. Their co-existence leads to diagnosis and treatment. There is no gold standard, all functions are non-specific. Numerical features such as blood pressure and proteinuria are defined by arbitrary thresholds. Thus, although these definitions appear to be accurate, they are unwarranted and there is still a great deal of uncertainty. Until recently, the accepted definition of PE was new-onset hypertension and proteinuria that developed in the second half of pregnancy and resolved after delivery. A more common and less dangerous form of new-onset hypertension without proteinuria is called gestational hypertension. 3 Figure 1 shows the international society for the study of hypertension in pregnancy (ISSHP)-endorsed classification of hypertension in pregnancy. 4 Current management of PE includes pre-counselling, prenatal blood pressure screening, patient-performed home blood pressure monitoring, 5 peripartum blood pressure control, management of complications, timely delivery, and monitoring. 6 Various approaches have been used to reduce the risk of PE in susceptible women, such as calcium supplementation, antioxidant therapy, and antiplatelet therapy, 7 but the only proven treatment for BE is childbirth.
Close observation of PE patients without severe symptoms before

Abstract
Ferroptosis is a novel form of regulated cell death typically characterized by nonapoptotic, iron-dependent, and reactive accumulation of oxygen species. Recent studies have found that ferroptosis plays an important role in the pathophysiology of pre-eclampsia (PE). In order to find potential therapeutic targets for ferroptosis intervention and better prevent the occurrence and progression of PE, the signalling pathways that regulate ferroptosis need to be identified. In this article, we review the role of vitamin D in PE and the role of ferroptosis in PE. Based on recent literature, we propose the scientific hypothesis that vitamin D can alleviate preeclampsia by modulating the ferroptosis signalling pathway. The aim of this review is to understand the regulatory pathways of ferroptosis in PE and to identify potential therapeutic targets.

K E Y W O R D S
ferroptosis, pre-eclampsia, signalling pathways 37 weeks of gestation is recommended, and delivery is recommended at 37 weeks of gestation.

| FERROP TOS IS AND PE
Ferroptosis, a new form of regulated cell death, is usually characterized by non-apoptotic, iron-dependent, and the accumulation of reactive oxygen species (ROS). 8  In particular, ferroptosis is involved in the pathological process of PE. Study found that ferroptosis in trophoblasts via the ferritinophagy pathway implicated in the pathogenesis of PE. 10 Reviews of the relationship between PE and ferroptosis have been reported. 11,12 In this article, we systematically summarize the pathways of ferroptosis and elaborate on the role of ferroptosis in PE, so as to provide intervention strategies for the pathways of ferroptosis in PE (Figure 2).

| VITAMIN D AND PE
Accumulating epidemiological studies support that Vitamin D deficiency is associated with the pathogenesis of preeclampsia. 13 Meanwhile, vitamin D deficiency is also associated with type 1 diabetes, 14 obesity, 15 and irritable bowel syndrome. 16 There is extensive literature on vitamin D deficiency increasing the risk of preeclampsia. 17 In a case-control study, disrupted vitamin D homeostasis and calcium transport was found in the placenta of PE cases. 18 A systematic review and meta-analysis found that micronutrient supplementation (calcium and vitamin D) interventions reduced the risk of developing PE. 19 Vitamin D is known to promote calcium absorption. Can calcium supplementation also reduce the risk of PE? A systematic review and network metaanalysis revealed that low-and high-dose calcium supplementation are effective for PE prevention in women with low calcium intake. 20 But there are also literature reports that vitamin D receptor gene polymorphism and vitamin D deficiency are not associated with the risk of preeclampsia. 21 This study was inconsistent with other studies, possibly due to the small sample size. In that case-control study, 40 preeclamptic and 40 normotensive pregnant women were compared for vitamin D status and vitamin D F I G U R E 1 Classification of hypertension in pregnancy. receptor gene polymorphism. 21 Taken together, there is more evidence that vitamin D or calcium supplementation can reduce the risk of PE.

| VITAMIN D AND FERROP TOS IS
There is no direct evidence that vitamin D supplementation reduces the risk of PE by modulating ferroptosis. Previous reviews have provided comprehensive coverage of the role of vitamin D and calcium supplementation in ferroptosis. 22 Calcium metabolism is closely related to iron metabolism. A review details that calciumiron connection plays an important role in eisenfohr-mediated neuronal cell death. 23 Apparently, calcium inhibits the absorption of iron in the gut. Calcium is a noncompetitive inhibitor of ferrous transporter 1 (DMT1) during intestinal iron absorption. 24 Calcium also induces the downregulation of genes related to iron absorption. 25 Another study also found that a low-calcium diet increased tissue iron levels in ovariectomized rats. 26 A case-control study found that total and ionized calcium were inversely associated with iron overload in children with transfusion-dependent thalassemia. 27 It is well known that iron overload is an important marker of ferroptosis. In conclusion, an imbalance in calcium homeostasis may be one of the most important causes of ferroptosis. Vitamin D supplementation can promote calcium absorption. One study suggested that oxidative stress may be associated with disruption of vitamin D homeostasis and placental calcium transport in PE patients. 28 Intake of calcium and potassium may play an important role in PE. 29 It is reasonable to speculate that vitamin D supplementation may inhibit iron absorption by promoting calcium absorption, and ultimately inhibit the occurrence of ferroptosis.
Based on recent literature, we propose the scientific hypothesis that vitamin D can alleviate preeclampsia by modulating the ferroptosis signalling pathway.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors declare that they have no conflicts of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
The datasets generated and analysed during the current study are available from the corresponding author upon reasonable request.