摘要
Background:Chronic endometritis(CE)is an important pathological factor contributing to female infertility and recurrent pregnancy loss.Although antibiotics are the primary clinical treatment for CE,they do not effectively improve pregnancy outcomes.Wen Yang Hua Zhuo(WYHZ)is a clinically employed classical formula known for its effects in warming yang,tonifying the spleen and kidneys,and resolving dampness.However,its underlying mechanisms remain unclear.This study aimed to elucidate how WYHZ modulates the immunometabolic microenvironment at the maternal-fetal interface in CE by targeting the MCT/HIF-1α/LDHA pathway to promote embryo implantation.Methods:In vivo,the model of CE was established by intrauterine injection of lipopolysaccharide(LPS)(1 mg/mL)into female C57/BL mice,followed by WYHZ treatment for 3 weeks to evaluate its effects on embryo implantation.Mechanistic studies were further conducted using the MCT-1 inhibitor AZD3965 and adeno-associated virus-mediated HIF-1αknockdown.In vitro,an in vitro CE model consisting of M1 macrophages and Ishikawa,as well as an in vitro embryo implantation model mediated by JAR cells,were constructed using Transwell,and the therapeutic mechanisms of WYHZ was validated using AZD3965 and lentiviral sh HIF-1αintervention.Metabolic enzyme activity assays,protein antibody microarrays,immunofluorescence,Western blotting,Seahorse analysis,and ELISA were employed.Results:WYHZ improved the immune-inflammatory microenvironment at the maternal-fetal interface by reducing pro-inflammatory cytokines and increasing anti-inflammatory factors.In parallel,WYHZ reprogrammed endometrial metabolism by enhancing glycolysis and suppressing mitochondrial oxidative phosphorylation,thereby improving endometrial receptivity and embryo implantation.Mechanistically,WYHZ activated the MCT/HIF-1α/LDHA pathway in endometrial epithelial cells,alleviating inflammatory stress and restoring receptivity.Both AZD3965 intervention and HIF-1αknockdown impaired endometrial receptivity and implantation,effects that were reversed by WYHZ.Conclusion:WYHZ modulates the immunometabolic microenvironment of the endometrium in the context of CE by targeting the activation of the MCT/HIF-1α/LDHA pathway,which improves endometrial receptivity and promotes embryo implantation.
基金
supported by the National Natural Science Foundation of China(grant number:82205172,82274570).
