Jianwei Shoutai Pills enhances maternal-fetal immune tolerance via regulatory T cell modulation to ameliorate uterine aging-associated early pregnancy loss.

BACKGROUND

Uterine aging constitutes a pivotal factor contributing to fertility decline and miscarriage among advanced maternal age women. Regulatory T (Treg) cells play a critical role in establishing maternal-fetal immune tolerance during embryo implantation, and have been shown to correlate significantly with early pregnancy loss in advanced maternal age women. Previous studies have demonstrated that Jianwei Shoutai Pill (JSP) effectively reduces early pregnancy loss; however, its regulatory mechanisms on Treg cells in the uterine aging-associated pregnancy loss remain elusive.

OBJECTIVE

To evaluate the therapeutic effects of JSP on early pregnancy loss associated with uterine aging and to explore the underlying mechanisms.

METHODS

JSP was characterized by UPLC-HRMS. Histopathological changes in uterine and E10.5 placental-uterine units were assessed via hematoxylin-eosin (HE) staining, Masson staining, and immunohistochemistry. Flow cytometry, real-time quantitative PCR (RT-qPCR), Western blot, and ELISA were used to evaluate Treg cell proportion and functional changes. Transcriptomics, metabolomics, network pharmacology, molecular docking, and molecular dynamics simulations were further employed to elucidate the potential mechanism of action of JSP.

RESULTS

JSP reduced the accumulation of senescent cells, collagen deposition, and inflammatory responses in the uterine tissue of aged mice, creating a favorable microenvironment for embryo implantation. JSP increased the proportion of decidual Treg cells by delaying age-related thymic involution. Integrated transcriptomic and metabolomic analyses revealed that JSP regulates energy metabolic reprogramming, enhances ATP levels to optimize the immunometabolic microenvironment at the maternal-fetal interface, and thereby improves Treg function, effectively reducing early miscarriage in aged mice. Network pharmacology, molecular docking, and molecular dynamic simulations further identified HIF-1α as a key target through which JSP regulates energy metabolic reprogramming. JSP was found to downregulate HIF-1α expression, reduce excessive lactate accumulation at the maternal-fetal interface, and restore ATP levels.

CONCLUSION

JSP inhibits thymic degeneration, increases the proportion of Treg cells in the placental-uterine unit, and optimizes the immune microenvironment at the maternal-fetal interface. Consequently, it restores the immunosuppressive function of Treg cells, enhances immune tolerance, and ultimately prevents miscarriage in aged mice. These findings demonstrate its therapeutic potential for pregnancy in advanced maternal age and elucidate a novel mechanism through which traditional Chinese medicine modulates uterine aging.