Intrauterine adhesions (IUAs), a leading cause of uterine infertility, present significant therapeutic challenges, with conventional treatments often yielding unsatisfactory reproductive outcomes. Although mesenchymal stem cell (MSC)-based therapies have demonstrated considerable promise, current biomaterial delivery systems face critical limitations, particularly in addressing the oxidative stress and inflammatory microenvironment of the damaged endometrium that impairs stem cell viability and function. Herein, we developed an injectable antioxidant hydrogel incorporating microspheres loaded with umbilical cord-derived MSCs (TPG hydrogel) for endometrial regeneration and fertility restoration. The TPG hydrogel was formed via dynamic phenylboronic ester crosslinking, endowing it with shear-thinning injectability for minimally invasive administration and potent reactive oxygen species (ROS) scavenging capacity to mitigate oxidative stress. This antioxidant microenvironment protected encapsulated MSCs from oxidative damage, thereby enhancing their therapeutic efficacy. Furthermore, the incorporation of EPLQLKM (E7) peptide-modified gelatin microspheres provided a bioactive niche that promoted cell adhesion and proliferation. Comprehensive in vitro and in vivo studies demonstrated that the TPG hydrogel exhibited dual functionality, including effective ROS scavenging and immunomodulatory effects characterized by the promotion of macrophage polarization toward the anti-inflammatory M2 phenotype. In a rat model of IUAs, the TPG hydrogel significantly enhanced endometrial regeneration and restored fertility. These findings highlight the TPG hydrogel as a promising therapeutic platform for the treatment of endometrial injury and fertility impairment associated with IUAs.

The vaginal epithelium, a hormone-sensitive barrier critical for reproductive health, lacks robust in vitro models due to primary tissue scarcity and existing systems’ limitations. Here, we established the first long-term, genetically stable human vaginal epithelial organoids (VEOs) using a tailored Matrigel-based culture medium that preserves the native stratified squamous architecture. Through transcriptomic and functional profiling, we identified progesterone as a key suppressor of immune defense and keratinization. Modeling Chlamydia trachomatis (CT) infection in VEOs recapitulated infection-induced reactive oxygen species (ROS) overproduction, senescence, and inflammation. Progesterone pretreatment significantly reduced ROS and cellular damage, suggesting hormonal modulation of cellular homeostasis. By integrating air-liquid interface (ALI) culture technique and exploring different proportions of Matrigel and collagen composition, we resolved the polarity limitations of three-dimensional (3D) organoids, enabling physiological modeling of infection-induced barrier dysfunction. This study establishes VEOs as a transformative model for dissecting hormone-microbe crosstalk in reproductive health and for accelerating therapeutic development against vaginal infections.

Summary Oocytes depend on maternal factors for maturation and early embryogenesis. Cytoplasmic lattices (CPLs) are distinctive fibrillar structures in mammalian oocyte cytoplasm implicated in maternal factor storage and developmental competence, yet their molecular composition and architecture remain elusive. Here, we use cryo-electron microscopy to resolve the high-resolution structure of native mouse oocyte CPLs. We identify 14 intrinsic components of multiple copies that assemble into filaments in which PADI6-mediated self-assembly and two subtypes of subcortical maternal complexes (SCMCs) form the core scaffold. Unexpectedly, we discover that α/β-tubulin dimers and two autoinhibited ubiquitination modules (UHRF1-UBE2D3, SKP1-FBXW18) are internal components of CPLs. We also uncover multivalent interactions that organize adjacent CPL filaments into higher-order helical bundles. By integrating CPL structure with biochemical and proteomic data, we propose a hierarchical assembly mechanism of CPLs, from subcomplexes to filaments to supramolecular lattices. Our study offers mechanistic insights into how maternal proteins are spatially organized to ensure successful early embryonic development and provides a structural foundation for understanding female infertility related to CPL-associated gene mutations.

Purpose:To identify the independent risk factors for placenta accreta spectrum (PAS) and assess the impact of endometrial thickness (EMT) on outcomes after transcervical resection of adhesions (TCRA) for intrauterine adhesions(IUA) prior to in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET). Methods:This single-center retrospective cohort study included 819 post-TCRA patients between March 2018 and March 2023. Propensity score matching (PSM) was used to balance baseline characteristics. Univariate and multivariate logistic regression analyses identified independent risk factors for PAS. Pregnancy outcomes (biochemical pregnancy, clinical pregnancy, live birth) and adverse obstetric outcomes (PAS, gestational diabetes, preterm delivery, low birth weight) were compared between EMT groups using different cutoffs (6-8 mm). Results:EMT and moderate-to-severe IUA were independent PAS risk factors (severe IUA: aOR=4.998, 95% CI:2.021~12.362). After PSM, the EMT <7 mm group had significantly lower live birth rates (40.3% vs. 55.7%,P=0.005) and higher rates of gestational diabetes,preterm delivery and low birth weight compared to EMT ≥7 mm. Using an 8 mm cutoff, the EMT <8 mm group consistently showed a higher PAS incidence both before (26.4% vs. 13.9%, P=0.001) and after PSM (26.4% vs. 14.7%, P=0.018). Conclusion:In post-TCRA IVF/ICSI-ET patients, EMT and IUA severity are independent PAS risk factors. EMT<7 mm worsens pregnancy outcomes, Exploratory analyses suggested that EMT <8 mm may be associated with higher PAS risk,but this finding requires validation in larger, prospective studies. Given the single-center retrospective design, these results should be interpreted as associative rather than causal. We think optimizing endometrial preparation to achieve a thickness of at least 8 mm may be crucial for reducing PAS and improving reproductive prognosis.

Background:The incidence of endometrial cancer among elderly women has been increasing year by year, and endometrioid endometrial carcinoma (EC) is the predominant histological subtype of endometrial cancer. Unfortunately, elderly patients with advanced-stage endometrioid EC continue to experience unfavorable prognostic outcomes. To date, reliable instruments for individualized prognosis estimation among elderly patients with stage III-IV endometrioid EC are still lacking. Therefore, this investigation sought to determine prognostic indicators and develop nomograms for the prediction of overall survival (OS) and cancer-specific survival (CSS) in this patient population. Methods:This study utilized data from the Surveillance, Epidemiology, and End Results (SEER) database, analyzing eligible elderly patients (aged ≥60 years) with stage III-IV endometrioid EC. The Kaplan-Meier approach was employed for survival analysis, while univariate and multivariate Cox regression analyses were used to identify factors independently associated with prognosis. Based on these characteristics, nomograms were constructed and subsequently evaluated via receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) to assess their discriminative performance, model fit, and potential clinical utility. Results:Multivariable Cox proportional hazards regression showed that age, tumor grade, N stage, chemotherapy, radiotherapy, surgery, and brain metastasis were independently linked to OS as well as CSS. The nomograms incorporating these variables demonstrated good predictive performance in both the training and validation cohorts. The calculated area under the curve (AUC) for OS ranged from 0.76 to 0.88, while those for CSS ranged from 0.77 to 0.84. Calibration curves demonstrated excellent agreement between the predicted and observed survival probabilities. Moreover, DCA indicated that the nomograms provided favorable net clinical benefits across a broad range of threshold probabilities. Conclusions:The constructed nomograms demonstrated satisfactory performance in predicting survival outcomes among elderly patients with advanced endometrioid EC, with good discriminatory ability. These models may facilitate individualized risk stratification, although further external validation is warranted before routine clinical application.

Programmed degradation of maternal proteins is essential for the oocyte-to-embryo transition (OET). While pharmacological inhibition studies have established the importance of proteasomes in ovarian reserve maintenance, oocyte maturation and fertilization, the physiological impact of intrinsic proteasome insufficiency and underlying molecular mechanisms remain poorly understood. In mice, endolysosomal vesicular assemblies (ELVAs), specialized membraneless compartments composed of proteasomes, endolysosomes and autophagosomes, facilitate protein degradation during oocyte maturation and early embryogenesis. In this study, we generated mice with oocyte-specific deletion of the proteasomal core subunit Psma7, to investigate the physiological function of the 20S proteasome and its roles in ELVAs-mediated protein degradation. PSMA7-deficiency destabilized 20S proteasomes and disrupted translocation of ELVAs, leading to pronounced accumulation of ubiquitinated proteins in oocytes and zygotes. Consequently, maternal Psma7 deletion resulted in female infertility, manifested by impaired oocyte maturation and developmental arrest at one- to two-cell stage. Furthermore, we observed reduced proteasome abundance and dysfunction of ELVAs in aged oocytes, providing a mechanistic explanation for the decline in developmental competence associated with oocyte aging. Taken together, our findings elucidate the critical function of proteasome-regulated proteostasis within ELVAs in maintaining oocyte quality during OET and reproductive aging. Proteasome activity has been implicated in the mammalian oocyte-to-embryo transition (OET). This study adopts oocyte-specific knockout of PSMA7, the α4 subunit of 20S proteasome, to investigate the role of proteasome in ELVAs formation, OET and reproductive aging, with implications for clinical diagnosis and treatment of poor oocyte quality. Oocyte-specific knockout of proteasomal PSMA7 subunit causes accumulation of ubiquitinated proteins and impairs cortical translocations of endolysosomal vesicular assemblies (ELVAs).

Preeclampsia (PE) is closely associated with alterations in placental extracellular vesicles (pEVs), but the mechanisms and their role in PE pathogenesis remain unclear. This study reveals that nicotinamide (NAM) levels in PE-derived pEVs (PE-EVs) are lower than in pEVs from normal pregnancies, correlating with disease severity. Functionally, NAM in pEVs inhibits Th1 differentiation via SIRT1 suppression and Th17 differentiation via macrophages. NAM-deficient pEVs exhibit reduced capacity to inhibit Th1 and Th17 cell differentiation both in vitro and in vivo, leading to PE-like symptoms. NAM is enriched in pEVs compared to placental villous tissue and maternal serum. The lower NAM in PE-EVs is due to decreased hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) expression in trophoblasts, which loads NAM into the cargo of multivesicular bodies (MVBs) via binding to the tryptophan-115 residue of HRS. Furthermore, the reduction of HRS in PE trophoblasts results from ubiquitination and degradation by elevated HSP27. Collectively, these findings indicate that elevated HSP27 in PE trophoblasts leads to the degradation of HRS, a reduction in pEV NAM levels, and diminished Th1 and Th17 inhibitory effects, thereby contributing to the development of PE.

Aging-induced decline in ovarian function and oocyte quality contributes to female infertility. However, the mechanisms underlying human umbilical cord-derived mesenchymal stem cell (HucMSC)-mediated rejuvenation of aged ovaries remain poorly understood. This study aimed to systematically investigate whether and how HucMSCs restore ovarian function and oocyte quality and elucidate the potential pathways involved. Aged mice received in situ ovarian injections of HucMSCs. Ovarian follicular development and fertility outcomes were assessed. Low-input RNA-seq and single-cell RNA sequencing (scRNA-seq) were applied to evaluate transcriptomic heterogeneity in oocytes and somatic cells separately. Additionally, the molecular change and function of HucMSC-primed stromal cells (SCs) in aged ovaries were assessed to validate SCs’ functional roles in ovarian microenvironment improvement. HucMSC treatment enhanced follicular development, increased antral follicle numbers, and partially restored fertility in aged mice. Oocyte transcriptomes in HucMSC-treated mice resembled those of young mice, with 75

Endometriosis is a debilitating, estrogen-dependent gynecological disorder characterized by profound diagnostic delays due to clinical reliance on invasive laparoscopy. Developing noninvasive, point-of-care biomarker assessment remains a critical yet unmet medical need. Here, we report an integrated electrochemical immunosensing platform (“Flower-CN-EC”) based on a structurally engineered, petal-like graphitic carbon nitride (g-C3N4) framework for the sensitive detection of urinary cytokeratin 19 (CK-19)-a promising candidate biomarker reflecting endometriosis-associated epithelial activity. The 3D hierarchical architecture of curled nanosheets provides an optimized microenvironment that facilitates unhindered mass transport and minimizes steric hindrance during covalent antibody immobilization. To bridge laboratory sensing with decentralized clinical translation, the sensor was coupled with a customized visual signal-processing interface featuring automated polynomial baseline correction. The sensor showed an excellent log-linear response to CK-19 (10 pg/mL-100 ng/mL), a low detection limit of 3.24 pg/mL, outstanding batch reproducibility (relative standard deviation 2.31%, n = 8), and exceptional ambient storage stability over 5 weeks. In a pilot clinical evaluation (n = 21), the platform successfully differentiated patients with histologically confirmed endometriosis from healthy controls with high statistical significance (p = 0.0011) and AUC of 0.899. These findings establish a robust, noninvasive proof-of-concept paradigm, paving the way for low-cost, decentralized endometriosis screening and longitudinal treatment monitoring.

Intrauterine adhesion (IUA) is an important cause of infertility and poses a challenge to women's reproductive health. However, conventional clinical treatments fail to fundamentally repair the function of the endometrium. While stem cell therapy is a promising breakthrough in IUA treatment, its clinical application remains limited. Recent studies have highlighted the pivotal roles of oxidative stress and inflammatory immune responses in IUA pathogenesis, underlining the requirement for excessive reactive oxygen species (ROS)-scavenging ability, where nanozymes demonstrated distinctive advantages. Herein, we report the preparation of a nanozyme-powered injectable hydrogel (HME) by integrating hollow estradiol-loaded MnO2 nanoparticles (MnO2@E2 NPs) with a hyaluronic acid-based hydrogel to explore its therapeutic effect in IUA. In vitro studies demonstrated that MnO2@E2 NPs exhibited catalase (CAT)-like and superoxide dismutase (SOD)-like enzymatic activities, effectively scavenging ROS. The HME possessed optimal mechanical properties, biocompatibility, robust antioxidant activities and regulatory properties on macrophages, thereby protecting human endometrial stromal cells (HESCs) and enhancing their proliferation. In a rat endometrial injury model, HME treatment regulated the uterine inflammatory microenvironment, suppressed M1 macrophage expression and further promoted endometrial repair. In conclusion, the HME offers a novel and effective therapeutic approach for IUA, with potential clinical implications for women of reproductive age.

Intrauterine adhesion (IUA) is a prevalent gynecological disorder characterized by endometrial fibrosis and compromised regeneration, with a lack of effective clinical treatments. Here, we present a microfluidic biofabrication strategy to engineer vascularized endometrial micro-organoids that recapitulate the cellular complexity and function of native tissue. By co-encapsulating human endometrial stromal cells, epithelial organoids, and endothelial cells (HUVECs) in biocompatible hydrogel microspheres, we created 3D constructs supporting hormone responsiveness, decidualization, and pathological remodeling upon transforming growth factor-βstimulation. Transcriptomic profiling and single-cell sequencing revealed that the presence of endothelial cells alleviated hypoxia-induced inflammation and promoted epithelial homeostasis.In vivotransplantation into a murine IUA model led to improved engraftment, endometrial regeneration, and fertility recovery. This vascularized organoid system offers a scalable and translational platform for endometrial repair and disease modeling, highlighting the promise of biofabrication in reproductive regenerative medicine.

Given the absence of evidence-based guidelines specifically addressing early pregnancy loss (EPL) management in IVF populations and the rising global volume of assisted reproductive treatments, there is an urgent clinical need to compare short-term uterine complications and subsequent reproductive outcomes across different management strategies to inform individualized counseling in this high-stakes fertility population. This retrospective cohort study included women with first-trimester early pregnancy loss after in vitro fertilization who were managed at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, between January 2015 and December 2022. Patients were classified according to the final completed management strategy: medical management, conventional vacuum aspiration without real-time ultrasound guidance, or ultrasound-guided vacuum aspiration. Inverse probability weighting was used to reduce baseline imbalances among the three groups. Because medical management and conventional vacuum aspiration were the two most frequently used strategies, a supplementary pairwise propensity score–matched analysis was performed to compare these approaches directly. The primary outcome was subsequent live birth. Secondary outcomes included retained products of conception, hysteroscopically detected intrauterine adhesion, pregnancy, clinical pregnancy, subsequent early pregnancy loss, mid-trimester miscarriage, and preterm birth. A total of 1,026 women were included, of whom 363 underwent medical management, 577 underwent conventional vacuum aspiration, and 86 underwent ultrasound-guided vacuum aspiration. Before weighting, live birth, retained products of conception, intrauterine adhesion, pregnancy, and clinical pregnancy rates differed significantly among the three groups. After inverse probability weighting, covariate balance generally improved. Weighted analyses showed significant intergroup differences in retained products of conception, clinical pregnancy, and live birth. Retained products of conception were most frequent after medical management and least frequent after ultrasound-guided vacuum aspiration. The weighted rates were 20.5

INTRODUCTION:Adenomyosis, which affects > 20% of reproductive-age women, is a major cause of infertility. Defective decidualization of endometrial stromal cells (ESCs) is a key pathogenic feature of adenomyosis; however, the underlying redox-metabolic mechanisms remain unclear. OBJECTIVES:This study aims to define how ferroptosis impairs decidualization and to investigate the cooperative role of solute carrier family 7 member 11 (SLC7A11) and the pentose phosphate pathway (PPP) enzyme glucose-6-phosphate dehydrogenase (G6PD) in maintaining redox homeostasis. METHODS:Eutopic endometrial tissues were obtained from 24 patients with adenomyosis and 22 fertile controls. A tamoxifen-induced mouse adenomyosis model (n = 20) and the pseudopregnancy decidualization assay were also used. Primary human ESCs were decidualized in vitro. Experimental approaches comprised RNA interference knockdown, adenoviral overexpression, stable-isotope tracing, liquid chromatography-mass spectrometry metabolomics, and iron modulation. Decidualization was assessed by evaluating insulin-like growth factor-binding protein 1 and prolactin expression, reactive oxygen species, lipid peroxidation, and nicotinamide adenine dinucleotide phosphate (NADPH)/NADP+ ratio. RESULTS:Ferroptosis was exacerbated in ESCs from patients with adenomyosis, as evidenced by elevated lipid peroxidation and iron accumulation alongside downregulated SLC7A11 and glutathione peroxidase 4. In both clinical samples and mice with adenomyosis, this ferroptotic phenotype correlated with impaired decidualization. Decidualization upregulated SLC7A11, enhancing the glutathione-based antioxidant system. SLC7A11 expression was positively associated with established markers of endometrial receptivity. Functional studies confirmed that SLC7A11 knockdown and pharmacologic inhibition both disrupted decidualization. Mechanistically, decidualization reprogrammed glucose metabolism, augmenting the PPP and its key enzyme G6PD to generate NADPH. SLC7A11 and G6PD acted synergistically to maintain redox homeostasis by supporting glutathione synthesis. Critically, this axis protected ESCs against iron overload-induced oxidative stress, rescuing decidualization defects. CONCLUSION:The SLC7A11-G6PD axis cooperatively counteracted ferroptosis during decidualization. SLC7A11-G6PD downregulation in adenomyosis resulted in oxidative damage and infertility. Pharmacological targeting of this redox axis may represent a novel therapeutic strategy for restoring endometrial receptivity in adenomyosis.

Intrauterine adhesion (IUA) is prevalent in women of childbearing age and can affect pregnancy outcomes or even lead to infertility. Currently, there is no effective clinical cure. We profiled more than 100, 000 human endometrial cells from IUA and normal endometrial tissues using single cell RNA sequencing (scRNA-seq), single nucleus transposase-accessible chromatin sequencing (snATAC-seq) and spatial transcriptomics to gain an in-depth understanding of the cellular and molecular mechanisms underlying IUA pathogenesis and enable the development of therapeutic targets. We investigated the diversity of fibrotic cell populations in human IUA. In addition to myofibroblasts, we identified a novel ACTA2 + KRT8+ myofibrotic-epithelial subpopulation and ACTA2 + CD31+ myofibrotic-endothelial subpopulation. The three fibrotic cell lineages were also detected in the rat IUA model. We also reconstructed the molecular differentiation trajectories and fibrotic molecular characteristics of the multiple fibrotic cell lineages. Extracellular matrix (ECM) related genes and fibrosis-related transcription factors (TFs) were highly expressed in the multiple fibrotic cell lineages in human and rat IUA. Finally, we revealed the pro-fibrotic immune microenvironment of IUA, in which the pro-fibrotic macrophage population was highly enriched in the IUA fibrotic niche and positively correlated with IUA clinical disease features. Macrophages can promote fibrotic gene expression in fibrotic cell populations through SPP1 and GALECTIN9. The changes in the fibrotic immune microenvironment showed high consistency in the human and rat IUA endometrium. Our study resolved the contribution of multiple fibrotic cell lineages and their interactions with the pro-fibrotic macrophages to endometrial fibrosis in IUA and provided therapeutic targets for IUA treatment.

Abstract Preeclampsia (PE), a major cause of maternal and perinatal mortality with highly heterogeneous causes and symptoms, is usually complicated by gestational diabetes mellitus (GDM). However, a comprehensive understanding of the immune microenvironment in the placenta of PE and the differences between PE and GDM is still lacking. In this study, Cytometry by time of flight (CyTOF) indicated that the frequencies of memory-like Th17 cells (CD45RA-CCR7+IL-17A+CD4+), memory-like CD8+ T cells (CD38+CXCR3-CCR7+Helios-CD127-CD8+) and pro-inflam Macs (CD206-CD163-CD38midCD107alowCD86midHLA-DRmidCD14+) were increased, while the frequencies of anti-inflam Macs (CD206+CD163-CD86midCD33+HLA-DR+CD14+) and granulocyte myeloid-derived suppressor cells (gMDSCs, CD11b+CD15hiHLA-DRlow) were decreased in the placenta of PE compared with that of NP, but not in that of GDM or GDM&PE. The pro-inflam Macs were positively correlated with memory-like Th17 cells and memory-like CD8+ T cells but negatively correlated with gMDSCs. Single-cell RNA sequencing revealed that transferring the F4/80+CD206- pro-inflam Macs with a Folr2+Ccl7+Ccl8+C1qa+C1qb+C1qc+ phenotype from the uterus of PE mice to normal pregnant mice induced the production of memory-like IL-17a+Rora+Il1r1+TNF+Cxcr6+S100a4+CD44+ Th17 cells via IGF1-IGF1R, which contributed to the development and recurrence of PE. Pro-inflam Macs also induced the production of memory-like CD8+ T cells but inhibited the production of Ly6g+S100a8+S100a9+Retnlg+Wfdc21+ gMDSCs at the maternal-fetal interface, leading to PE-like symptoms in mice. In conclusion, this study revealed the PE-specific immune cell network, which was regulated by pro-inflam Macs, providing new ideas about the pathogenesis of PE.

The extracellular matrix (ECM) constantly remodels to tailor a temporal spatial specific environment for the residing cells to respond to physiological or pathological stimuli. Endometrial mesenchymal stem cells (eMSC) are excellent therapeutic candidates for treating endometrial problems. In-depth investigation of the native niche to understand the regulatory mechanisms of the stem cells will enable greater translational potentials in regenerating the thin or damaged endometrium. To understand the ECM niche of eMSC, endometrial ECM from full thickness human endometrial tissues at different menstrual phases are preserved by tissue decellularization and then transformed into hydrogel material (EndoGel). EndoGel exhibits excellent compatibility with eMSC by enhancing the expansion of eMSC in vitro and facilitating the therapeutic regenerative effect in vivo evidenced by the improved fertility outcome. Comparative study of the proliferative to secretory phase EndoGel reveals unique matrisome at specific phase of the human menstrual cycle. The post-regenerated endometrium shows distinct transcriptomic profile when transplanted with different menstrual phase EndoGel, suggesting the regulatory effect of the tissue matrix is menstrual phase specific. This is the first study comparing the endometrial matrix from specific human menstrual cycle and exploring its therapeutic potentials as a supportive biomaterial for eMSC to enhance endometrial regeneration.

Research question Does pinopode detection or endometrial receptivity analysis (ERA) improve personalized embryo transfer (PET) outcomes in patients with recurrent implantation failure (RIF) more effectively? Design This retrospective study analysed 488 patients with RIF: 222 underwent pinopode detection, 81 underwent ERA and 185 served as controls without any testing. Propensity score matching was used to mitigate confounding factors, resulting in matched pairs: 108 pinopode controls, 66 ERA controls and 66 pinopode ERA. Results In matched pairs, the pinopode group showed significantly higher rates of embryo implantation (41.55% versus 27.01%, P = 0.002), biochemical pregnancy (69.44% versus 53.70%, P = 0.017), clinical pregnancy (60.19% versus 43.52%, P = 0.014) and live birth (53.70% versus 33.33%, P = 0.003) compared with controls. The ERA showed marginal non-significant improvements. In comparison, the pinopode group had a higher clinical pregnancy rate than the ERA group (63.64% versus 45.45%, P = 0.036). Among patients with the window of implantation (WOI) displacement, the pinopode group had a significantly higher clinical pregnancy rate (66.67% versus 43.59%, P = 0.045). Conclusions Pinopode detection significantly improves clinical pregnancy outcomes in patients who have had RIF compared with controls and ERA, particularly in cases of window of implantation displacement. Prospective studies with larger cohorts are needed to validate these findings and to assess the potential for standardizing pinopode detection in clinical practice.

Polycystic ovary syndrome (PCOS) patients with hyperandrogenemia exhibit an increased risk of early pregnancy loss; however, the underlying mechanisms remain poorly understood. Ferroptosis, an iron‐dependent form of cell death driven by phospholipid peroxidation, has been implicated in various diseases. This study identifies significant iron homeostasis disorders and ferroptosis in PCOS patients with hyperandrogenemia, which is mediated by androgen‐induced reduction of ferritin heavy chain 1 (FTH1) protein levels in trophoblasts. Specifically, androgens upregulate FTH1 mRNA and protein synthesis by binding to androgen response elements on the FTH1 promoter via the androgen receptor (AR). Simultaneously, elevated androgen levels enhance chaperone‐mediated autophagy (CMA) through upregulating LAMP2A (lysosomal‐associated membrane protein 2), thereby promoting FTH1 protein degradation. When androgen levels are excessive or AR is overactivated, this CMA‐driven degradation exceeds FTH1 protein synthesis, leading to a reduction in FTH1 level. Furthermore, metformin was found to compete with androgens for AR binding, thereby stabilizing FTH1 and protecting trophoblasts from ferroptosis. In PCOS‐model mice, metformin significantly reduced early embryonic absorption. These findings reveal androgen‐induced ferroptosis as a key mechanism in placental dysfunction and highlight a potential application of metformin for treatment of early pregnancy loss associated with PCOS.