Preeclampsia (PE) is the second leading cause of maternal mortality worldwide and contributes significantly to maternal morbidity, including proteinuria, hepatic and renal dysfunction, and cardiovascular and cerebrovascular complications (Rana et al., 2019). PE is also associated with adverse neonatal outcomes, such as fetal growth restriction, increased disease susceptibility, and perinatal death (Ma'ayeh et al., 2020). The condition involves placental dysregulation, resulting in intravascular and placental inflammation and immune imbalance (Miller et al., 2022). A hallmark of PE is the disrupted balance between regulatory T cells (Tregs) and effector T cells, characterized by an upregulation of pro-inflammatory T helper (Th)1 and Th17 responses and a concurrent downregulation of anti-inflammatory Th2 and Treg subsets (Murray et al., 2021). Furthermore, the frequency and cytotoxicity of pro-inflammatory T cells are elevated in PE compared to normal pregnancy (de Groot et al., 2010; Lager et al., 2020), underscoring the therapeutic potential of targeting T cell responses.

The pathophysiology of PE is influenced by epigenetic modifications, particularly DNA methylation (Apicella et al., 2019). Among these, 5-methylcytosine (m5C), catalyzed by specific methyltransferases, is a key post-transcriptional modification (Dou et al., 2020). Elevated global m5C levels have been observed in placental tissues from PE patients (Wilson et al., 2019). Methyl CpG binding protein 2 (MeCP2), an m5C-binding regulator, plays a crucial role in DNA methylation and immune regulation. MeCP2 has been implicated in cancer prognosis and is associated with altered immune cell infiltration in osteosarcoma (Zhang et al., 2021a). In neurological disorders such as multiple sclerosis and neuromyelitis optica spectrum disorder, MeCP2 mediates anti-inflammatory responses, as evidenced by changes in cytokine profiles and immune regulatory gene expression (Mehmood et al., 2023). Notably, MeCP2 silencing enhances lipopolysaccharide (LPS)-induced myometrial contraction, suggesting a role in preterm labor (Tang et al., 2019; Peng et al., 2024). However, whether MeCP2 modulates PE progression through effects on immune T cells remains unclear.

Secreted frizzled-related protein 4 (SFRP4) is upregulated in severe PE and contributes to placental angiogenesis and apoptosis (Vidal et al., 2022). Elevated SFRP4 expression is associated with programmed cell death ligand-1 (PD-L1) positivity and increased CD8+ T cell infiltration in gastric cancer (Yu et al., 2022). SFRP4 is also predicted to correlate with various T cell phenotypes in heart failure and osteoarthritis (Wen et al., 2023). Importantly, MeCP2 has been shown to attenuate cardiomyocyte oxidative stress, cell cycle arrest, and apoptosis via modulation of the SFRP4 pathway, mitigating hypoxia/reperfusion injury. Despite these findings, the interplay between MeCP2 and SFRP4 in PE pathogenesis remains poorly defined.

This study aimed to elucidate the role of MeCP2 in PE, with a focus on its immunomodulatory functions. Our findings demonstrate that MeCP2 negatively regulates SFRP4 expression in PE and modulates immune cytokine production and T cell phenotypes. These results support a potential role for the MeCP2/SFRP4 axis in the immunotherapeutic management of PE.