Recurrent spontaneous abortion (RSA) is a distressing disorder affecting numerous women of reproductive age. N6-methyladenosine (m6A) RNA modification is a crucial epigenetic regulator, but its role in RSA remains elusive. ALKBH5 (AlkB homolog 5) is a pivotal m6A demethylase that erases m6A marks to positively regulate target gene expression. This research examines the role of the m6A demethylase ALKBH5 in the decidualization process associated with RSA. Decidual tissues from RSA patients and healthy controls were collected. ALKBH5 was knocked down or overexpressed in primary human endometrial stromal cells (ESCs). Decidualization was induced using medroxyprogesterone acetate and 8-Br-cAMP. Phenotypes were assessed via morphology, qPCR, ELISA (for IGFBP1/PRL), and Western blotting. RNA-seq, MeRIP-qPCR, dual luciferase reporter assay, and bioinformatics were applied to determine targets and mechanisms, and immunohistochemistry was used to assess protein expression in decidual tissues. ALKBH5 was downregulated in RSA decidual tissues but upregulated during in vitro decidualization. ALKBH5 knockdown inhibited the morphological transformation and reduced the expression and secretion of decidual markers IGFBP1 and PRL. RNA-seq and intersection analysis identified BMP2 as a key candidate target. Mechanistically, ALKBH5 knockdown increased m6A methylation on BMP2 mRNA, leading to decreased BMP2 expression. Conversely, ALKBH5 overexpression reduced BMP2 m6A levels and enhanced BMP2 expression, which further potentiated decidualization. Importantly, BMP2 knockdown reversed the pro-decidualization effects of ALKBH5 overexpression. Clinically, a strong positive correlation was observed between ALKBH5 and BMP2 expression levels in both the HC group and the RSA group. Furthermore, the ROC curve results indicate that either ALKBH5 or BMP2 could serve as a better diagnostic factor for patients with RSA. ALKBH5 promotes endometrial decidualization by demethylating BMP2 mRNA and enhancing its expression. The downregulation of the ALKBH5-BMP2 axis contributes to decidualization deficiency and may represent a novel epigenetic mechanism underlying RSA.

Uterine arteriovenous fistula (UAVF) associated with adenomyosis during pregnancy is a rare, life-threatening condition. This report describes a 36-year-old woman with adenomyosis who conceived through in vitro fertilization-embryo transfer and experienced recurrent vaginal bleeding in early pregnancy, followed by spontaneous miscarriage at 14 weeks. One month post-miscarriage, she developed a delayed massive hemorrhage. Color Doppler ultrasound revealed mosaic blood flow signals and high-velocity low-resistance spectra (resistance index 0.52) within the myometrium, confirming acquired UAVF. Emergency uterine artery embolization achieved successful hemostasis while preserving bilateral uterine artery trunks. Menstruation resumed 3 months postoperatively. This case raises the hypothesis of a possible association between adenomyosis and pregnancy-related UAVF. In patients with adenomyosis who are pregnant, recurrent early bleeding that is unresponsive to conservative therapy should raise suspicion for underlying vascular abnormalities, and color Doppler ultrasound evaluation may be warranted. Delayed explosive post-miscarriage hemorrhage refractory to uterotonics is characteristic. UAE is the preferred fertility-sparing treatment, with individualized embolization strategies and long-term follow-up essential.

Recurrent pregnancy loss (RPL) is a multifactorial reproductive disease that is typified by repeated pregnancy loss with immune dysregulation emerging as a critical contributing factor. Immunoglobulins are among the immune components that are instrumental in preserving tolerance between the mother and the fetus, regulating inflammatory responses, and supporting placental development. This review provides a comprehensive overview of the role of immunoglobulins in recurrent pregnancy loss, with particular emphasis on immune dysregulation, emerging biomarkers, and therapeutic implications. The immunoglobulin profiles, such as the changes in IgG subclasses and the presence of pathogenic autoantibodies, e.g. antiphospholipid and antinuclear antibodies, are highly correlated with unfavourable pregnancy outcomes. These changes, in a mechanistic manner, lead to poor trophoblast invasion, endothelial dysfunction, thrombosis and cytokine imbalance. Emerging evidence also highlights the contribution of regulatory B cells and the antibody-mediated immune network in maintaining pregnancy homeostasis. Immunoglobulin profiling has clinical potential as a diagnostic and prognostic methodology that can be used to stratify patients and provide customised therapy. Immunomodulatory therapies, especially intravenous immunoglobulin (IVIG), are potentially effective in a limited range of patient populations, but clinical response is variable. On the whole, this review demonstrates the role of immunoglobulin-mediated mechanisms in RPL and their future potential in enhancing precision medicine approaches to better diagnosis and management.

The maternal-fetal interface (MFI) serves as a crucial bidirectional crosstalk site between the mother and the developing fetus, wherein precisely orchestrated immune regulatory networks are indispensable for sustaining tolerance toward the semi-allogeneic fetus while concurrently defending effectively against pathogenic challenges. Excessive inflammatory activation can perturb immune homeostasis at the MFI, particularly during the first trimester, and can compromise placental development and function, thereby contributing to adverse pregnancy outcomes, including recurrent spontaneous abortion, preeclampsia of placental origin, and even aberrant embryonic development. Therefore, a detailed understanding of the cellular composition of the MFI and its dynamic relationship with placental development is fundamental to elucidating disease etiology and informing interventional research on placenta-related pregnancy complications. This review summarizes the major immune cell populations present at the MFI (namely T cells, decidual Natural Killer cells and decidual macrophages) and their functional characteristics, examines their roles in physiological placental formation and remodeling, and evaluates their associations with several common adverse pregnancy outcomes. Collectively, the findings highlight the central role of major maternal immune cells in establishing immune tolerance during early gestation and underscore the potential clinical value of immune profiling in predicting and managing adverse pregnancy outcomes.

Recurrent pregnancy loss (RPL) is a heterogeneous reproductive condition, and unexplained recurrent pregnancy loss (URPL) denotes repeated pregnancy losses for which no established cause is identified after standard evaluation. Recurrent miscarriage (RM) and recurrent spontaneous abortion (RSA) are overlapping terms used in the literature, whereas recurrent implantation failure (RIF) is a related but distinct infertility context. In this Mini Review, URPL is treated as an exclusion-based clinical category rather than a single disease entity. This review examines the hypothesis that a subset of URPL reflects abnormalities in specific cellular and molecular components of the maternal-fetal interface. We focus on maternal compartments, including endometrial epithelial lineage states, decidual stromal dysfunction, and stromal-immune interactions, as well as fetal/trophoblast compartments such as trophoblast lineage defects and broader maternal-fetal interactions, incorporating insights from recent advances in molecular and cellular technologies and human model systems. Particular attention is given to single-cell, spatial, organoid, assembloid, implantation model, trophoblast stem cell, and placental explant studies published from 2024 to 2026. Current data do not establish clinical subtypes for URPL or support treatment selection in routine practice. However, recent molecular and cellular technologies now make it possible to define interface phenotypes with higher resolution and to test whether patient-derived abnormalities are reproducible and perturbable in experimental systems. An interface-centered framework may therefore help move URPL research from broad exclusion-based labels toward experimentally testable subtype identification based on epithelial, decidual, trophoblast, immune, and embryo-endometrial phenotypes.

The present investigation seeks to clarify the molecular underpinnings through which perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) precipitate recurrent miscarriage (RM). Initially, prospective targets of PFOA (6050 in total) and PFOS (8896 in total) were systematically compiled from three repositories-CTD, ChEMBL, and Super-PRED-while 1822 pathogenic targets linked to RM were cataloged through the amalgamation of GeneCards, OMIM, and NCBI resources. Venn diagrammatic assessment disclosed 699 overlapping targets shared between PFOA and RM, alongside 832 shared between PFOS and RM. Thereafter, PPI networks were assembled utilizing the STRING platform. By applying median filtering coupled with CytoHubba-based evaluation, central targets were distilled-362 for the PFOA-RM axis and 502 for the PFOS-RM axis-together with their respective top 10 hub genes. Functional enrichment conducted via DAVID pointed toward platelet coagulation elements as potentially critical mediators in PFOA- and PFOS-triggered RM. Moreover, the distinctive enrichment of transcriptional co-regulatory complexes observed specifically for PFOS, coupled with divergent pathway involvements including adipocytokine signaling, TNF cascades, and fluid shear stress transduction between the two agents, implies compound-specific pathogenic modalities. Overlapping target scrutiny pinpointed TP53 as the exclusive pathogenic gene candidate. SMART-based verification affirmed its essential structural domains, with documented subcellular residence in cytoplasmic, nuclear, and mitochondrial compartments. TP53 engages functionally with MDM2 and MDM4 among other interactors, exhibiting pronounced expression within female reproductive tissues such as the cervix and ovary. Notably, its expression proved markedly elevated in healthy villous tissues (encompassing cytotrophoblast and chorionic cavity cells) relative to decidual counterparts. Single-cell interrogation further substantiated prominent TP53 expression within migratory extravillous trophoblasts, extravillous trophoblast populations, and endometrial vascular endothelial cells. Ex vivo investigations demonstrated that PFOA and PFOS exposure markedly suppressed HTR8/Svneo cell proliferation while promoting programmed cell death, concomitantly attenuating TP53 protein abundance. Computational molecular docking corroborated favorable binding energetics between both perfluorinated compounds and the TP53 protein. Collectively, these observations furnish novel mechanistic perspectives on PFAS-driven RM pathogenesis, highlighting TP53 as a promising molecular marker for environmentally triggered RM. Also, this study is limited by its in vitro nature, the use of a single SV40-immortalized trophoblast cell line, and the absence of primary human trophoblast or organoid validation.

Recurrent pregnancy loss (RPL) continues to be a significant challenge in reproductive medicine, particularly in women for whom standard examinations do not reveal a conclusive underlying reason. There is growing evidence that several instances may result from nuanced alterations in the endometrial milieu, particularly with decidualization and maternal-fetal immune tolerance. In recent years, vitamin D has gained recognition for its significance in early pregnancy, serving not only as a regulator of calcium metabolism but also as an active contributor to endometrial and immunological functions. The human endometrium exhibits the vitamin D receptor (VDR) and the enzyme CYP27B1, facilitating the local activation and signaling of vitamin D inside the uterine milieu. Experimental investigations have shown that vitamin D influences many processes critical for effective implantation and placentation, including stromal cell differentiation, cytokine equilibrium, trophoblast invasion, oxidative stress responses, and immune cell communication. Aberrant vitamin D signaling has been associated with heightened inflammatory activity, impaired decidual transformation, altered uterine natural killer cell functionality, and alteration of the Treg/Th17 equilibrium, all of which have been implicated in recurrent pregnancy loss. Concurrently, there is an increasing emphasis on the association between vitamin D and mitochondrial function as well as oxidative stress in decidual and endometrial cells. Interruption of these pathways may influence implantation and early embryonic development by impacting cellular metabolism and immunological control at the maternal-fetal interface. The clinical interest in vitamin D supplementation for women experiencing repeated reproductive failure is increasing; nevertheless, the existing results are conflicting, mostly due to the predominance of research focusing on circulating vitamin D levels rather than localized tissue-specific processes. Our review encapsulates new findings about the function of vitamin D in endometrial biology and reproductive immune regulation, emphasizing its involvement in decidualization, inflammatory signaling, oxidative stress, and maternal-fetal immunological tolerance in recurrent pregnancy loss. The potential ramifications for assisted reproduction and forthcoming tailored therapy techniques are also examined.

Recent studies have indicated the relationships between the human reproductive system, gut microbiota and immune crosstalk. These interactions can influence pregnancy outcomes, which occasionally result in adverse consequences for the mother and fetus. However, key questions remain unresolved, such as identifying the microbiota capable of modulating immune cells during pregnancy. The present review aimed to investigate the relationship between microbiota and T cell types and to clarify the mechanism through which these interactions occur. In pregnancy‑related disease models, it is still unclear whether T helper cell (Th17)/regulatory T cells (Treg cells) are generated in situ or migrate into inflamed tissues. The present review explored the association of gastrointestinal dysbiosis with the female reproductive system and the role of the maternal‑fetal interface. In particular, the effect of gut microbiota‑derived short‑chain fatty acids, bile acids, indoles and their derivatives on immune signaling networks is discussed. Furthermore, the effects of these networks on infectious, metabolic and female pregnancy periods are summarized. Finally, the translational potential of modulating gut microbiota through probiotics and dietary interventions to restore immune homeostasis and improve pregnancy outcomes in Recurrent pregnancy loss (RPL) is also evaluated. The present review aimed to assist patients in developing a more profound comprehension of the underlying causes of unexplained RPL and broaden the spectrum of potential therapeutic strategies for infertility.

Recurrent spontaneous abortion (RSA) is a major reproductive health challenge with limited clinical options. Curcumin, a natural polyphenol widely consumed as a dietary supplement, has shown promise in improving pregnancy outcomes; however, its specific molecular targets remain obscure due to its broad bioactivity. This study aimed to define curcumin's impact on RSA and identify its direct molecular target to provide a mechanistic basis for its nutritional application. We employed an integrated approach combining phenotypic analysis in the RSA mouse model and target discovery in human endometrial stromal cells. Target identification was performed using unbiased Limited Proteolysis-Mass Spectrometry (LiP-MS). The interaction between curcumin and the identified target, BRD4, was confirmed through molecular docking, dynamics simulations, functional genetics, and chromatin immunoprecipitation (ChIP-qPCR). Functional outcomes were assessed by measuring key ferroptosis markers and mitochondrial morphology using transmission electron microscopy. Decidualization was analyzed in both mouse tissues and cells subjected to a decidualization and ferroptosis induction protocol. Curcumin significantly reduced embryo resorption and restored decidual morphology and marker expression (PRL and IGFBP1) in RSA mice. LiP-MS analysis in human decidual stromal cells identified ferroptosis as the primary pathway targeted by curcumin. Both in vivo and in vitro validation showed that curcumin inhibits ferroptosis, decreasing lipid peroxidation, restoring glutathione balance, and preserving mitochondrial integrity, which in turn rescued decidual marker expression. Proteomic integration with ferroptosis databases identified BRD4 as a central hub. Mechanistically, curcumin binds BRD4, thereby suppressing BRD4-driven expression of TFRC and ACSL4, which blocks ferroptosis and rescues decidual markers. This research uncovers a BRD4-driven ferroptosis pathway as a key pathogenic mechanism in RSA. Our results demonstrate that curcumin acts as an epigenetic modulator by directly targeting BRD4, thereby suppressing this pro-ferroptotic transcriptional program. These findings provide critical mechanistic evidence supporting curcumin as an evidence-based nutritional intervention for RSA.