Work

Shoutai pill promotes endometrial decidualization and prevents recurrent spontaneous abortion through dual regulation of apoptosis and ECM remodeling by the LDHA-lactate axis

Year: 2025

Type: article

Abstract: Recurrent spontaneous abortion (RSA), a common condition, predominantly affects the reproductive system of women of childbearing age. Due to the unique physiological complexity of pregnancy and etiological heterogeneity, RSA is difficult to diagnose and treat clinically. As normal embryonic development depends on specific metabolic processes to maintain an optimal microenvironment, aerobic glycolysis has recently attracted considerable attention as a critical metabolic pathway. The traditional formula Shoutai Wan (STW) has shown obvious clinical effects in the treatment of RSA. However, the underlying molecular mechanisms of STW in managing RSA remain unclear and require further investigation. To investigate the mechanism by which STW alleviates early pregnancy loss by maintaining glycolytic activity and the acidic microenvironment (AME) in decidual tissues in RSA mice, and by regulating the ERK1/2/HIF-1α signaling pathway to reduce abnormal apoptosis in decidual tissues, restore extracellular matrix (ECM) remodeling, and promote decidual maturation. Mice were randomly divided into four groups: control, model, dydrogesterone (DYD), and STW. The RSA model was established in all groups except the control. Control and model mice received equivalent volumes of saline via gavage, while DYD (0.2 mL/20 g/day) and STW (0.3 g/20 g/day) groups received corresponding treatments. After 14 consecutive days, females were co-housed with males (2:1 ratio). On gestation day (GD) 6, embryos and the MFI were collected for pathological assessment, including: (1) MFI microenvironment (pH, lactate content); (2) glycolytic metabolism (key enzyme activities/expressions, lactate transporter expression); (3) ERK1/2/HIF-1α signaling pathway (p-ERK1/2, HIF-1α); (4) apoptosis and related factors (Bcl-2/Bax/Caspase-3), apoptosis rates (TUNEL, flow cytometry); (5) ECM remodeling markers (MMP-2, MMP-9, TIMP-1, TIMP-2, Desmin) and decidualization markers (IGFBP-1). The embryo loss rate was calculated on GD14. Additionally, the effects of STW-treated serum on human endometrial stromal cells (hESCs) were examined in vitro to validate the mechanisms. In comparison to the control group, RSA model mice showed a higher level in terms of embryo loss rate, disrupted AME characteristics at the MFI, increased pH, and reduced lactate content. Decreased lactate inhibited activities and expressions of key glycolytic enzymes (HK2, PKM2, LDHA). Downregulation of the ERK1/2/HIF-1α signaling axis resulted in increased apoptosis, impaired ECM remodeling (reduced expressions of MMP-2, MMP-9, TIMP-1/2, and Desmin), and decreased expression of the decidualization marker IGFBP-1. STW and DYD treatments effectively reversed these abnormalities and significantly reduced embryo loss rates. STW demonstrated superior efficacy over DYD, particularly in inhibiting apoptosis and promoting ECM remodeling, confirmed by in vitro experiments. Aerobic glycolysis and AME homeostasis at the MFI function as crucial metabolic hubs for maintaining pregnancy. Dysfunction of this system triggers pathological changes, including excessive apoptosis of decidual cells, impaired ECM remodeling, and disrupted decidualization through the ERK1/2/HIF-1α signaling pathway. The core therapeutic mechanism of STW involves effective remodeling of this metabolic-signaling regulatory network, thereby improving early pregnancy outcomes, and promoting embryo implantation. • High Light • In RSA model mice, the embryo loss rate is increased, and the maternal-fetal interface exhibits characteristics of AME disruption, specifically manifested by elevated pH value and decreased lactic acid content. • In the RSA model, lactic acid production is reduced, and the activity and expression of key glycolytic enzymes (HK2/PKM2/LDHA) are inhibited. This further downregulates the ERK1/2/HIF-1α signaling axis, leading to increased cell apoptosis, ECM remodeling disorders, and decreased expression of the decidualization marker IGFBP-1. • Both STW and DYD can reverse the aforementioned abnormalities in the RSA model and reduce the embryo loss rate. Notably, STW shows superior efficacy over DYD in inhibiting cell apoptosis and promoting ECM remodeling. • The aerobic glycolysis-AME homeostasis at the maternal-fetal interface is a metabolic hub for maintaining pregnancy. STW can improve pregnancy outcomes by remodeling the "metabolism-signaling" coordinated regulatory network, providing a potential effective strategy for RSA treatment.

Source: Journal of Ethnopharmacology

DOI: 10.1016/j.jep.2025.121077