Jiawei Shoutai Pill promotes embryo implantation via PPAR signaling and endometrial microbiota remodeling: An integrative multi-omics study.

BACKGROUND

Recurrent implantation failure (RIF) remains a major barrier to successful assisted reproductive technology, given the lack of effective, mechanism-informed interventions to enhance endometrial receptivity. Jiawei Shoutai Wan (pills) (JWSTW), a modified formulation of the classic Shoutai Pill (STP) used in reproductive medicine, has not been systematically evaluated in the treatment of RIF, and its bioactive components and molecular targets remain largely unclear.

PURPOSE: To determine whether JWSTW improves implantation competence and to identify the pathways associated with its effects.

MATERIALS AND

METHODS

A mifepristone-induced embryo implantation dysfunction (EID) rat model was established to evaluate implantation outcomes, uterine histology, and markers of endometrial receptivity and vascular perfusion. Bulk uterine transcriptomics and peripheral blood serum untargeted metabolomics were integrated with liquid chromatography-tandem mass spectrometry (LC-MS) based component profiling, network pharmacology, multi-omics correlation analysis, uterine cavity microbiota profiling and structure-based computational analyses. Key pathway molecules were further assessed using targeted molecular experiments. A retrospective cohort of RIF patients undergoing assisted reproduction was analyzed for ultrasound-derived endometrial receptivity parameters before and after treatment.

RESULTS

JWSTW administration improved implantation outcomes in EID rats, characterized by the upregulation of multiple receptivity- and perfusion-associated tissue markers. Integrated multi-omics analyses identified peroxisome proliferator-activated receptor (PPAR) signaling and lipid metabolism as significantly enriched pathways, supported by corresponding gene-metabolite correlations. Animal experiments using PPAR agonists (rosigitazone) and antagonists (T0070907) further confirmed that the PPAR pathway is a primary target of JWSTW. JWSTW was also associated with structured changes in the uterine cavity microbiota, with enriched taxa and predicted functions aligned with lipid metabolism related pathways. LC-MS/MS characterization identified sweroside and loganic acid as major circulating constituents, while computational analyses prioritized a PPAR-centered target network with favorable binding affinity and structural stability. In the retrospective RIF cohort (n = 100), JWSTW was associated with increased endometrial thickness and improved Doppler-derived perfusion indices.

CONCLUSION

These results demonstrated that JWSTW enhances endometrial receptivity and promotes embryo implantation in RIF by modulating the PPAR-lipid metabolism axis and remodeling the uterine microbiota. Consequently, our study advances the pharmacodynamic understanding of JWSTW and deepens the comprehension of its underlying mechanistic basis in RIF. Furthermore, these findings provide an innovative Traditional Chinese Medicine-based treatment strategy, offering a promising therapeutic avenue for patients with RIF.