Tiaojing Cuyun Recipe inhibits ferroptosis through SLC7A11/GSH/GPX4 axis to improve endometrial receptivity of mice with embryo implantation dysfunction

Tiaojing Cuyun Recipe (TJCYR), a known Chinese herbal compound, has been shown to improve endometrial receptivity and embryo implantation in patients with embryo implantation dysfunction (EID). This study investigated the mechanism by which TJCYR improves endometrial receptivity. High-performance liquid chromatography (HPLC) was used to detect the compounds of TJCYR. A mouse EID model was established by subcutaneous injection of mifepristone into the neck. The rats were randomized into control, EID, Prog, TJCYR-L, and TJCYR-H groups. Hematoxylin and eosin (H&E) staining and transmission electron microscopy (TEM) were performed to assess pathological changes in the endometrium. The aggregation of Fe 3+ was assessed using Prussian blue staining. Western blotting, immunofluorescence, and assay kits were used to determine the endometrial receptivity, ferroptosis indicators, and SLC7A11/GSH/GPX4 axis-related biomarkers. TJCYR-H group significantly increased the implanted sites ( P < 0.05), improved endometrial pathological changes and enhanced the expression of progestogen receptor (PR), estrogen receptor α (ERα), leukocyte inhibitory factor (LIF), osteopontin (OPN), integrin αV, SLC7A11, GPX4 (glutathione peroxidase 4), and ferritin, as well as the serum estradiol (E 2 ), progesterone (Pg), reduced glutathione (GSH), glutathione peroxidase (GSH-Px), and T-GSH levels in EID. TJCYR inhibited the reduction in mitochondrial volume and membrane shrinkage, increased density, and decreased cristae in endometrial glandular epithelial cells of EID. Furthermore, TJCYR reduced the aggregation of Fe 3+ , downregulated serum MDA and GSSG levels, and reduced the expression of cyclooxygenase-2 (COX2), 4-hydroxy-2-nonenal (4-HNE), acyl-CoA synthetase long-chain family member 4 (ACSL4), and transferrin receptor (TFR) in EID mice. TJCYR can improve endometrial receptivity of EID mice by inhibiting ferroptosis, which may be related to the SLC7A11/GSH/GPX4 axis.