Tianxiang Ni

Recurrent pregnancy loss (RPL) is a distressing pregnancy disorder experienced by ~2.5% of women who try to conceive. Dysregulation of decidual function is an important factor leading to RPL, but the underlying genetic factors remain unknown. We discovered that the methyltransferase SETD1B and a non‐coding circular RNA (circSTK40) were significantly down‐regulated in the decidual tissue of RPL patients compared to those with healthy pregnancies. SETD1B knockdown resulted in increased apoptosis, decreased autophagy, and increased glycolysis, which could disrupt decidual function among those with RPL. Circstk40 overexpression upregulated SETD1B and alleviated apoptosis, lactic acid accumulation, and autophagy inhibition. Mechanistically, circSTK40 bound to both SETD1B and histone H3, promoting interactions between the two proteins and consequently increasing H3K4 methylation levels. H3K4me2 and H3K4me3 modifications in the SETD1B promoter enhanced transcription of this gene, forming a putative positive feedback loop between SETD1B and H3K4me2/H3K4me3. SETD1B and circSTK40 coordinately promoted decidua survival and function for pregnancy maintenance. Our findings reveal a novel molecular mechanism underlying RPL, providing valuable targets for future research into functional RPL treatments.

Objective: To investigate the relationship between the number of previous implantation failures (IFs) and embryo ploidy status, as well as subsequent clinical outcomes, in women with recurrent implantation failure (RIF) undergoing preimplantation genetic testing for aneuploidy (PGT-A). Methods: This retrospective cohort study included 422 women with RIF who underwent their first PGT-A cycle between 2017 and 2022. Participants were stratified by maternal age (p < 0.001). Ploidy distribution did not differ significantly across IF categories. Among women aged p = 0.012). Neonatal weight did not differ significantly across IF categories. Conclusions: The number of previous IFs was not independently associated with embryo ploidy or clinical outcomes after euploid transfer, whereas advanced maternal age was strongly associated with a lower likelihood of obtaining euploid embryos. In younger women with ≥5 IFs, a greater number of previous embryo transfer attempts was associated with live birth after euploid transfer; however, this exploratory subgroup finding should be interpreted cautiously and requires prospective validation. Because this study did not directly evaluate therapeutic strategies, any potential role for individualized endometrial evaluation or optimization should be considered as hypothesis-generating rather than supported by the present data.

Defective endometrial receptivity represents an important factor in recurrent implantation failure (RIF), though its precise regulatory mechanisms remain unclear. While nicotinamide N-methyltransferase (NNMT) is abundantly expressed in human endometrial tissues, its role in endometrial receptivity and RIF pathogenesis has not been defined. This study demonstrated that NNMT expression was significantly downregulated in midluteal-phase endometrium from RIF patients relative to fertile controls. Functional analyses in human endometrial stromal cells (ESCs) revealed that NNMT knockdown enhanced autophagy flux and disrupted progesterone signaling. Mechanistically, NNMT deficiency elevated H3K9me3 enrichment at the Aldh1a3 promoter, suppressing its expression. Notably, knockdown of ALDH1A3 resulted in similar effects with NNMT downregulation, and exogenous rhALDH1A3 reversed the autophagy alterations and rescued progesterone signaling in NNMT-knockdown cells. In vivo, NNMT inhibition in a murine model reduced embryo implantation rates and decreased ALDH1A3 expression. Collectively, these findings indicate that reduced NNMT impairs endometrial receptivity through H3K9me3-mediated ALDH1A3 repression, leading to aberrant autophagy and disrupted progesterone signaling in decidualized ESCs. This study identifies the NNMT-H3K9me3-ALDH1A3 axis as a key epigenetic-metabolic pathway underlying RIF, offering novel diagnostic and therapeutic targets.

The efficacy of preimplantation genetic testing for aneuploidy (PGT-A) in couples with unexplained recurrent pregnancy loss (uRPL) may vary according to the number of good-quality blastocysts available. This study is to determine whether PGT-A could improve the cumulative live birth rate (CLBR) among couples experiencing uRPL as the number of high-quality blastocysts increases. A retrospective study involving 1073 couples with uRPL was conducted at a university-affiliated reproductive center. Patients were divided into two groups: 813 participants who underwent PGT-A and 260 participants who underwent conventional in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). A stratified analysis was conducted, which categorized the female participants into three subgroups based on the number of high-quality blastocysts: 1–3, 4–6, and ≥ 7. A binary logistic regression model was used to evaluate the associations between the number of high-quality blastocysts and the cumulative pregnancy outcomes. Among uRPL patients undergoing PGT-A or IVF/ICSI, there were respectively 421 vs. 129 with 1–3 blastocysts, 252 vs. 69 with 4–6 blastocysts, and 140 vs. 62 with ≥ 7 blastocysts. In 1–3 blastocysts subgroup, CLBR was 23.52% after PGT-A vs. 33.33% after IVF/ICSI (adjusted OR 1.005, 95% CI 0.604–1.674, p = 0.984). In 4–6 blastocysts subgroup, CLBR was 53.17% after PGT-A vs. 75.36% after IVF/ICSI (adjusted OR 0.398, 95% CI 0.197–0.802, p = 0.010). In ≥ 7 blastocysts subgroup, CLBR was 73.57% after PGT-A vs. 66.13% after IVF/ICSI (adjusted OR 1.660, 95% CI 0.729–3.799, p = 0.227). In these three subgroups, clinical pregnancy loss rates were all similar between the two treatment methods. In women with uRPL, PGT-A did not improve CLBR, irrespective of the number of high-quality blastocysts available. Routine use of PGT-A in this population is therefore not recommended. Future high-quality randomized controlled trials may better define its appropriate indications.

Regulatory T (T _reg ) cells play a vital role in maintaining maternal immune tolerance to the semiallogeneic fetus during pregnancy. T _reg cell population heterogeneity and tissue-specific functions in the human decidua remain largely unknown. Here, using single-cell transcriptomic and T cell receptor sequencing of human CD4 ⁺ T cells from first-trimester deciduae and matched peripheral blood of pregnant women, we identified a highly activated, immunosuppressive CCR8 ⁺ T _reg cell subset specifically enriched in the decidua (dT _reg cells). CCR8 ⁺ dT _reg cells were decreased in patients with recurrent pregnancy loss (RPL) and an abortion-prone mouse model. Depletion of CCR8 ⁺ dT _reg cells increased susceptibility to fetal loss, with altered decidual immune profiles. Adoptive transfer of CCR8 ⁺ T _reg cells rescued fetal loss in abortion-prone mice. The CCR8 ligand CCL1 was mainly produced by decidual CD49a ⁺ natural killer cells and was significantly decreased in patients with RPL. Our data demonstrate that CCR8 ⁺ dT _reg cells are required to maintain maternal-fetal tolerance and highlight potential avenues for RPL therapies.

The history and development of reproductive genetics span centuries of scientific exploration and technological innovation. Today, the importance of offspring health and further understanding of the relevant molecular mechanisms and interdisciplinary knowledge have led to significant advancements, which are gradually appearing in clinical settings. However, whether this rapid progress in reproductive genetics could lead to technical, ethical, and economic problems warrants evaluation. This brief review introduces a range of approaches to reproductive genetics, from the earliest to the most recent, and discusses future concerns regarding the large-scale use of emerging reproductive genetic tools.

Background: Alterations in lipid metabolism were reported to impact human fertility; however, there is limited evidence on the association of lipid metabolism with embryo implantation as well as the etiology of recurrent implantation failure (RIF), especially regarding arachidonic acid metabolism.Methods: Experimental verification research (16 RIF patients and 30 control patients) based on GEO database analysis (24 RIF patients and 24 control patients). The methods in bioinformatics included differential gene screening, functional enrichment analysis, protein‐protein interaction network, cluster analysis, weighted gene co‐expression network analysis, and so forth. RIF patients were recruited for the experimental validation section. The endometrial samples in the mid‐luteal phase were collected and subjected to quantitative real‐time PCR detection.Results: Genes related to oxidative stress were differentially expressed and 17 different types of immune cells exhibited diverse infiltration in three RIF subgroups with different arachidonic acid metabolism. HPGDS, ALOX12, and TBXAS1 showed a strong positive correlation with the infiltration of NK cell, on the contrary, GGT6, PLA2G12A, and PTGS2 showed a strong negative correlation. The overall expression of AAMRGs was positively correlated with the infiltration of activated CD8 T cell, macrophage, natural killer cell, and T follicular helper cell.Conclusions: The cluster of arachidonic acid metabolism‐related genes (AAMRGs) was abnormally expressed and positively associated with excessive oxidative stress as well as extensive infiltration of immune cells, including NK cells among RIF patients. Considering the high heterogeneity of the etiology of RIF, our study utilized the expression of AAMRGs as a typing basis to provide a new understanding of endometrial receptivity from the perspective of lipid metabolism and immune regulation in unexplained RIF couples, providing directions for its etiology and future basic research.