Preeclampsia (PE) is a multi-system disorder that classically presents with newly onset hypertension after 20 weeks of gestation, complicated by at least one other end-organ dysfunction, such as proteinuria, renal dysfunction, pulmonary edema, and fetal growth restriction [
1]. PE infringes on 4.6% of pregnant women worldwide [
2,
3] and 2.3% of all pregnancies in China [
4], and remains a major cause of maternal and perinatal morbidity and mortality [
5]. Regardless of the timing of onset, all PE patients are at risk of rapid deterioration into hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome or eclampsia [
6‐
8], posing a huge burden to healthcare across the world. Except for these short-term risks, the long-term impact, such as cardiovascular, renal, and cerebrovascular events, posed a threat to both the mothers and their offsprings [
9‐
12]. The etiology of PE remains largely unknown, but placental dysfunction is thought to be the core pathological change for PE. According to the two-stage model, placental dysfunction (stage 1), featured by oxidative stress, mitochondrial dysfunction, metabolism disorder, and apoptosis [
13,
14], is the initiating event for the subsequent maternal disease (stage 2) by releasing soluble toxic materials into the maternal circulation [
15]. During this process, multiple pathogenic processes, including angiogenic imbalance, immune cell activation, and endothelial cell dysfunction were involved [
16‐
18], but the underlying molecular mechanism remains obscure. Currently, delivery of the fetus is the definite treatment of PE, however, preterm and the long-term risk of complications have brought impediments to PE management. Pharmaceutic therapies have been used in PE management. For example, aspirin is recommended for PE prevention in high-risk pregnant women [
19]. Other small molecules, such as statins and metformin, have been shown to reduce adverse outcomes and incidence of PE [
20,
21]. However, there is still a great gap between the treatment options and clinical needs, especially in fetal outcomes. Therefore, a comprehensive understanding of pathogenesis and novel agent development will be of capital importance to PE treatment. Autophagy, an intracellular degradation system for damaged or dysfunctional cellular components, plays a capital role in maintaining cellular homeostasis [
22]. It is also the core molecular pathway that regulates embryo development during normal pregnancies [
23]. Intervention in normal autophagy processes will lead to a plethora pathologies, including cancers, metabolic disorders, and many others [
24]. Recently, increasing evidence suggests that autophagy is associated with PE [
25‐
27], however, these studies provided conflicted results. For example, Akaishi et al. [
28] reported a decreased level of p62, a substrate of autophagy, indicating activated autophagy in PE placentas. On the contrary, Nakashima et al. [
29] observed the accumulation of p62 in placental samples from PE patients, suggesting inhibited autophagy in PE. Such a contrast may be result of a complex regulation network and the microenvironment that autophagy involves in. Therefore, a thorough understanding of correlations between autophagy and PE as well as its microenvironment may lead to finding novel targets for PE and the development of novel therapeutics.
Despite minimal treatment options for PE, development of novel therapies is ongoing, including pravastatin, Metformin, and aspirin. However, due to the high demand for safety profiles in pregnant women, safety equals to or even outweighs effect in drug development for PE. In China, medicinal herbs have been a major treatment option for thousands of years, including the pregnant women. Studies [
30‐
32] accumulated that some active ingredients of herbs, such as berberine, baicalein, and luteolin, can exert a protective effect against PE. For example, berberine (BBR), a major component isolated from
Coptis chinensis, is active on multiple organs in the human body. Studies showed that BBR can regulate metabolic disorders, reduce hypertension, and alleviate preeclampsia by regulating IL-2/IL-10 balances and inhibiting apoptosis [
33,
34]. Baicalein (BCL), a flavonoid extracted from
Scutellaria baicalensis Georgi, is known for its antitumor effect in various malignancies. It was reported that BCL reduced blood pressure by regulating inflammatory and vascular disease-related factors in hypertensive pregnant rats [
35]. Also, BCL was reported to protect liver and kidney function by inhibiting apoptosis in a PE model [
36]. As
S. baicalensis Georgi is one of the herbs that were most frequently prescribed for and used by pregnant women [
37], BCL seems to be a potential agent with a good safety profile for PE. In addition, luteolin was found to be a candidate for PE treatment by reducing anti-angiogenic sFlt-1 releasing and promoting vasorelaxation of uterine arteries [
38,
39]. However, whether these active ingredients can target autophagy remains obscure. Therefore, this study aims to identify novel autophagy-related targets of PE and eventually find a safe therapeutic for PE by drug screening. First, a weighted gene co-expression network analysis (WGCNA) was applied to filter autophagic hub genes that related with PE. The differential expression levels and regulatory network of hub genes were also validated with two independent datasets and analyzed via specific toolkits, respectively. Associations between the hub genes and the infiltrated immune cells were analyzed to explore the role of autophagy in PE microenvironment. Additionally, as the potential therapeutics for PE, berberine, baicalein, and luteolin were screened by molecular docking in comparison to pravastatin, metformin, and aspirin.