BACKGROUND:Preeclampsia (PE) remains a leading cause of maternal and perinatal morbidity. Women of advanced maternal age (AMA, ≥ 35 years) constitute a rapidly expanding high-risk subpopulation in China. Existing first-trimester prediction models were derived in general obstetric populations and often rely on specialized biophysical or proprietary biomarker assays, with limited validation in AMA women. METHODS:This multicenter retrospective study enrolled 2,582 AMA pregnant women from three tertiary centers in southern China, partitioned into a training cohort (n = 1,327), an internal validation cohort (n = 569), and two external validation cohorts (n = 399 and 287). Predictors were selected using LASSO and multivariable logistic regression and assembled into a nomogram. Performance was evaluated by area under the receiver operating characteristic curve (AUC), calibration, Brier scores, decision curve analysis, and clinical impact curves. RESULTS:Seven independent predictors were retained: pre-pregnancy BMI, parity, mode of conception, uric acid, white blood cell count, red blood cell count, and hemoglobin. The nomogram achieved AUCs of 0.819, 0.795, 0.787, and 0.756 across the four cohorts, with close calibration and favorable net benefit. Performance was preserved when women with chronic hypertension were included and across early-onset and late-onset PE subgroups. Notably, maternal age itself was not discriminative within the AMA stratum (P = 0.626). CONCLUSIONS:This nomogram relying exclusively on routine clinical and laboratory parameters provides an accessible tool for individualized early-pregnancy PE risk assessment and risk-stratified antenatal management in AMA women.

Background Preeclampsia (PE) is a life-threatening pregnancy disorder wherein placental hypoxia contributes significantly to its pathogenesis. This study aimed to identify and characterize hypoxia-related biomarkers for PE and to evaluate their potential value. Methods We analyzed the GSE75010 and GSE54618 datasets by weighted gene co-expression network analysis (WGCNA) to identify gene modules associated with PE. GO and KEGG enrichment analyses were performed, followed by intersection with a known hypoxia-related gene set and construction of a protein-protein interaction network. A two-gene nomogram (P4HA1 and INHA) was established using the GSE75010 dataset, and its diagnostic value was evaluated by area under the curve (AUC) and calibration curves in the validation cohorts GSE60438 and GSE25906. For experimental validation, RT-qPCR, Western blot, and immunohistochemistry assessed P4HA1 and INHA expression in human placentas. Finally, an L-NAME-induced PE mouse model and a CoCl2-induced trophoblast hypoxia model further verified their expression and function. Results We identified P4HA1 and INHA as key genes. The two-gene nomogram showed moderate diagnostic performance in validation cohorts. Both genes were elevated in PE placentas and localized to trophoblasts. Hypoxia upregulated their expression in vivo and in vitro. Knockdown of either gene partially restored trophoblast migration, invasion, and proliferation under hypoxia, and combined silencing produced a greater recovery. Conclusions This study identified P4HA1 and INHA as key hypoxia-responsive genes in PE, offering a new molecular perspective on disease pathogenesis.

Background: Preeclampsia (PE) is a leading cause of maternal-fetal morbidity, yet first-trimester predictive biomarkers anchored in maternal inflammation remain lacking. Current screening relies predominantly on placental angiogenic markers that under-perform for late-onset PE (LOPE). Whether inflammation-related circulating proteins can improve early prediction and how they participate in PE pathogenesis have not been established. Methods: A stepwise biomarker discovery was conducted across four independent first-trimester serum cohorts (n = 475) using non-targeted proteomics, parallel reaction monitoring, and ELISA. Predictive modelling employed Firth’s bias-reduced logistic regression. The cellular origin of the candidate biomarker was determined by flow cytometric intracellular staining and single-cell RNA sequencing analysis. Mechanistic studies were performed in THP1 monocytes (stable knockdown and overexpression) with RNA sequencing and Western blot, and in complementary loss- and gain-of-function pregnant mouse models. Findings: Serum peroxiredoxin-2 (PRDX2) was reproducibly downregulated at 11–14 weeks of gestation in women who subsequently developed PE, with superior discriminative capacity over PLGF, PAPPA, and MAP (AUC = 0.848), particularly for LOPE (AUC = 0.882). A composite model integrating PRDX2, PLGF, and MAP achieved AUCs of 0.897 (cross-validation) and 0.892 (real-world cohort). The circulating PRDX2 deficit originated from peripheral monocytes rather than the placenta. Inflammatory stimuli suppressed monocyte PRDX2 protein, while PRDX2 knockdown activated NF-κB/MAPK signalling, amplified pro-inflammatory cytokine secretion, and dysregulated the chemokine profile. PRDX2 knockdown exacerbated, and PRDX2 overexpression ameliorated, hypertension, proteinuria, and systemic inflammation in LPS-induced pregnant mice. Interpretation: Our findings identify first-trimester serum PRDX2 as a reproducible, inflammation-anchored predictive biomarker for PE, particularly for LOPE. Mechanistically, monocyte PRDX2 deficiency establishes a self-reinforcing inflammatory circuit contributing to PE pathogenesis, highlighting the monocyte PRDX2-inflammatory axis as a potential target for preventive strategies.

Emerging evidence indicates a correlation between the triglyceride-glucose (TyG) index and gestational diabetes mellitus (GDM). However, its predictive efficacy for GDM in pregnancies with advanced maternal age has not been conclusively established. This study sought to assess the predictive utility of the TyG index for GDM specifically among pregnant women of advanced maternal age. This retrospective cohort study included 635 advanced maternal age pregnant women (164 diagnosed with GDM). First-trimester clinical and biochemical indicators were collected, and a machine learning method was employed to construct a prediction model to evaluate the role of the TyG index in GDM risk prediction. The Gradient Boosting model incorporated seven key predictors: TyG index, maternal age, pre-pregnancy body mass index, platelet count, uric acid, low-density lipoprotein, and high-density lipoprotein. The optimized model demonstrated exceptional discriminative performance, achieving an AUC of 0.963 and a prediction accuracy of 0.901. DCA confirmed that the model provided significant net clinical benefit for identifying high-risk GDM cases in advanced maternal age pregnancies. It demonstrated favorable clinical application potential. The first-trimester TyG index exhibits robust predictive capability for GDM onset in pregnant women of advanced maternal age, underscoring its potential as a valuable clinical biomarker.

Pre-eclampsia is a significant obstetric complication. Immune cells within the maternal circulatory system hold substantial promises for the diagnosis and treatment of pre-eclampsia. However, research focusing on the maternal circulatory system remains inadequate. We conducted differential analysis and weighted correlation network analysis on a dataset to identify blood biomarkers for early-onset pre-eclampsia. These biomarkers were subsequently validated through ELISA. Multiple bioinformatic analyses were subsequently performed to predict the biological functions associated with the selected genes and potential protein‒miRNA regulatory relationships. Additionally, by analysing single-cell transcriptomic data from blood samples, we predicted the genetic profiles of the selected genes, investigated changes in the proportion of blood immune cells and abnormalities in intercellular communication in the pathogenesis of pre-eclampsia, and predicted potential protein-compound interactions. We identified and validated the expression levels of F2R-like trypsin receptor 1 (F2RL1) and granzyme H (GZMH) in maternal blood samples obtained from women with and without pre-eclampsia. Gene set enrichment analysis revealed that F2RL1 participates in the regulation of classic signaling pathways, including the Toll-like receptor signaling pathway, pattern recognition receptor signaling pathway, oxidative stress-induced endogenous apoptosis signaling pathway, and vesicle targeting process. GZMH primarily contributes to immune processes associated with natural killer cells. Analysis of single-cell sequencing datasets revealed significant alterations in T cells and haematopoietic stem cell growth factor (HSC-G-CSF) within the maternal blood system during the onset of pre-eclampsia. Furthermore, receptor–ligand interaction analysis and protein–compound interaction analysis highlighted the critical role of aspirin in alleviating pre-eclampsia pathology, while also revealing the potential therapeutic value of tyrosine kinase inhibitors. This study identified the pre-eclampsia biomarkers F2RL1 and GZMH, which showed good diagnostic value. This research provides new insights for the prediction of pre-eclampsia and deepens our understanding of changes in the maternal blood immune system during pre-eclampsia.

Gestational diabetes mellitus (GDM) is a common metabolic disorder that affects maternal and fetal health. O-GlcNAcylation is increased in GDM and disrupts placental homeostasis. This study aimed to explore the role of O-GlcNAcylation in GDM progression and the underlying mechanism. Trophoblast cell line (HTR-8/SVneo) was treated with high glucose (HG) to assess a cell model. Ferroptosis was evaluated by lipid reactive oxygen species (ROS), malondialdehyde, Fe2+, and glutathione concentrations. The GDM mouse model was established, and blood glucose and blood lipid were measured. The effect of OGT on ELP3 O-GlcNAcylation was measured using immunoprecipitation and western blotting. The results showed that ferroptosis was involved in HG-induced cell injury, and OGT expression was increased in these cells (over 3-fold). Knockdown of OGT inhibited HG-induced ferroptosis in vitro (P < 0.01), and reduced blood glucose (P < 0.01), blood lipid (P < 0.01), and ferroptosis (P < 0.01) in GDM mice. Moreover, silencing of OGT reduced ELP3 protein stability (P < 0.01) via inhibiting ELP3 O-GlcNAcylation at Ser408 site. Overexpression of ELP3 abrogated the inhibition of ferroptosis in HG-induced cells caused by OGT knockdown (P < 0.01). In conclusion, silencing of OGT inhibits trophoblast ferroptosis by suppressing O-GlcNAcylation of ELP3, thereby ameliorating GDM. The findings suggest that targeting OGT-mediated O-GlcNAcylation may be a promising strategy for GDM treatment.

Preeclampsia (PE), a hypertensive disorder unique to pregnancy, is linked to impaired trophoblast function. DEAD-box helicase 39B (DDX39B) plays key roles in embryonic development. This study investigated its role in regulating trophoblast biology during PE progression. We conducted functional assays using CCK-8, clone formation, EdU, Transwell, Wound healing and TUNEL in the HTR-8/SVneo trophoblast cells. The interaction between Wilms tumor 1-associating protein (WTAP) and DDX39B was analyzed by Co-IP assay. RIP assay or RNA pull down were used to assess the association between the ELAV-like RNA-binding protein 1 (ELAVL1)/WTAP and L-lactate dehydrogenase A (LDHA) mRNA. Additionally, MeRIP assay was employed to evaluate m6A levels on LDHA transcripts. Overexpression of DDX39B promoted the proliferation and migration of trophoblast cells and suppressed cells apoptosis, while DDX39B knockdown had the opposite result. In addition, WTAP knockdown reversed the promoting effects of DDX39B overexpression on trophoblast proliferation and migration. Mechanistically, DDX39B promoted post-translational stabilization of WTAP by directly interacting with WTAP protein. WTAP enhanced the m6A methylation of LDHA mRNA by recruiting ELAVL1. As expected, LDHA knockdown abrogated the pro-proliferative and anti-apoptotic effects of WTAP overexpression on trophoblasts. Our findings established a novel DDX39B/WTAP/m6A/LDHA regulatory axis, wherein DDX39B acted as an RNA-binding protein to stabilize WTAP, enhancing LDHA expression and promoting trophoblast proliferation, migration, and survival. Dysregulation of this pathway might contribute to PE pathogenesis, offering new avenues for targeted therapies.

Preeclampsia (PE) is a pregnancy-specific complication and there remains no effective treatment. Given the limitations on medication use during pregnancy, exploring natural, safe, and effective drugs for PE is worthwhile. We investigate the causal relationship between ferroptosis, inflammation, and PE, and determine the protective effects of quercetin (QCT), a representative compound that is classified as a flavanol, against endothelial dysfunction. Then, the target of QCT is predicted and verified. The prophylactic addition of a low dose of QCT rescues endothelial dysfunction, aiding in endothelial repair. Furthermore, QCT alleviates PE-like maternal manifestations and endothelial dysfunction in the placenta of the selective reduced uteroplacental perfusion (sRUPP) rat model through binding to the epidermal growth factor receptor (EGFR). The potential applications of QCT are expanded, offering the possibility of further development as a safe and effective preventive molecule for PE. The flavanol quercetin rescues endothelial dysfunction and preeclampsia-like manifestations in a pre-clinical model via inhibition of ferroptosis and inflammation.

Onasemnogene Abeparvovec (Zolgensma) is a gene therapy for the treatment of Spinal Muscular Atrophy (SMA) with improved motor neuron function and the potential for a singular treatment. Information on its adverse drug reactions is mainly from clinical trials and real-world studies with extensive sample sizes are lacking. In this study, we analyzed the U.S. Food and Drug Administration’s Adverse Event Reporting System (FAERS) database to assess the drug safety profile of Zolgensma. A total of 1951 adverse event reports associated with onasemnogene abeparvovec (Zolgensma), containing 778 import important medical event (IME) signals, were identified from the FAERS database, and multiple disproportionate analysis algorithms were used to determine the significance of these adverse events. This study identified 281 onasemnogene abeparvovec-related adverse events (AEs), including some significant adverse events not mentioned in the product labelling. Elevated liver enzymes, fever, vomiting, and thrombocytopenia were the most common adverse reactions. Most adverse events manifested within the initial month of onasemnogene abeparvovec use, especially the first 8 days, but some may still occur after 1 year of treatment. Sex-specific scrutiny revealed differing risk levels for adverse events among women and men. Thrombocytopenia and thrombotic microangiopathy are more common in patients weighing ≥8.5 kg, and changes in renal function need to be closely monitored if thrombotic microangiopathy occurs. The above findings provide valuable insights into optimizing the utilization of onasemnogene abeparvovec, improving its effectiveness, and minimizing potential side effects, thereby greatly facilitating its practical application in clinical settings.

AIM: To evaluate alterations in conjunctival vascular density (CVD) and macular capillary density (MCD) in female patients with type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM) using optical coherence tomography angiography (OCTA). METHODS: A total of 60 female participants were recruited, comprising 20 patients with T2DM, 20 patients with GDM, and 20 healthy age-matched controls (HCs). OCTA was used to assess superficial and deep retinal and conjunctival capillary plexuses. Subsequently, changes in MCD were analyzed using a circular segmentation method (C1-C6), a hemispheric quadrant segmentation method [superior right (SR), superior left (SL), inferior left (IL), and inferior right (IR)], and the early treatment diabetic retinopathy study (ETDRS) segmentation method (S, I, R, L). RESULTS: OCTA unequivocally demonstrated that the variations in CVD among HCs, T2DM, and GDM groups were statistically significant (P<0.001). In the superficial retinal capillary plexus (sRCP), significant differences were observed in the densities of total microvascular (TMI), microvasculature (MIR), and macrovascular (MAR) between patients with T2DM and HCs (P<0.05). Furthermore, the GDM group exhibited a more substantial reduction in MIR density compared to the T2DM group (P<0.01). In the deep retinal capillary plexus (dRCP), significant differences in the densities of TMI and MIR were identified between the T2DM group and HCs (P<0.05), with a notable difference in TMI density also observed between the GDM and T2DM groups (P<0.01). In the receiver operating characteristic (ROC) curve analysis, the area under the ROC curve (AUC) for TMI in sRCP between the T2DM group and HCs was 0.975, with a 95% confidence interval (CI) of 0.941–1. The AUC for MIR was highest in dRCP, with an AUC value of 0.914 and a 95%CI ranging from 0.847 to 0.981. In comparing the GDM and T2DM groups, the AUC for I region was maximized in sRCP, achieving a value of 0.978 with a 95%CI of 0.953–1. Additionally, the AUC for R region was maximized in dRCP, reaching a value of 0.99 with a 95%CI of 0.975 to 1. CONCLUSION: The sRCP and dRCP densities show higher diagnostic sensitivity for T2DM and GDM. OCTA holds potential as a significant instrument for the early diagnosis and differentiation of T2DM and GDM.

PURPOSE:Preterm premature rupture of membranes (PPROM) is a major contributor to preterm birth and is associated with increased risks of maternal and neonatal complications. The aim of this review is to summarize current antibiotic strategies and explore emerging adjunctive therapies, including probiotics, amnioinfusion, and fetal membrane repair, to improve the management of PPROM. METHODS:Relevant literature on antibiotic therapy for PPROM and emerging treatment strategies was systematically retrieved from PubMed. The data were analyzed to compare standard antibiotic protocols with personalized and combination regimens. RESULTS:Evidence indicates that adjusting antibiotic duration and adopting precision-based regimens may improve clinical efficacy while minimizing adverse effects. Moreover, probiotics, amnioinfusion, and fetal membrane repair hold promise in alleviating infection-related inflammation and improving pregnancy outcomes. CONCLUSIONS:Optimizing antibiotic therapy via individualized approaches and incorporating adjunctive treatments could enhance the management of PPROM. Future research ought to concentrate on pinpointing biomarkers for personalized antibiotic selection, evaluating combination therapies, and assessing long-term maternal-fetal outcomes.

Preeclampsia (PE) is a complex gestational disorder marked by vascular abnormalities and elevated blood pressure yet remains without widely effective treatments. This study investigates the efficacy of ferulic acid (FA) in alleviating PE symptoms by targeting the signal transducer and activator of transcription 3 (STAT3)/vascular endothelial growth factor (VEGF) signaling axis to enhance endothelial integrity and reduce inflammation. An NG-nitro-l-arginine methyl ester hydrochloride (l-NAME)-induced PE mouse model was used, with FA administration to pregnant mice to assess therapeutic effects on key outcomes such as blood pressure, proteinuria, and placental function. Single-cell RNA sequencing (scRNA-seq) and molecular assays were conducted to examine FA's impact on endothelial cell balance, inflammation, and pathway-specific activity. The results showed that FA treatment significantly reduced hypertension, proteinuria, and inflammation, while improving endothelial cell balance in PE mice. In addition, inhibition of STAT3 phosphorylation by FA enhanced endothelial barrier function, stabilized vascular integrity, and supported improved fetal development outcomes. Overall, these findings demonstrate the protective effects of FA in PE by alleviating endothelial impairment and dampening inflammatory activity, offering a promising strategy to improve maternal and fetal health in PE, with implications for managing pregnancy-related vascular dysfunctions.NEW & NOTEWORTHY Our study investigates ferulic acid (FA) as a potential therapeutic intervention for preeclampsia (PE), a severe pregnancy complication with limited treatment options. By targeting the STAT3/VEGF signaling pathway, FA demonstrated significant reductions in hypertension, inflammation, and improved endothelial cell balance in PE mice. These results highlight FA's promise in enhancing maternal and fetal health by addressing endothelial dysfunction, suggesting its potential for broader applications in managing pregnancy-related vascular dysfunctions.

Background Human decidual mesenchymal stem cells (hDMSCs) play crucial roles in pregnancy. The decreased resistance of hDMSCs to oxidative stress is a key factor contributing to recurrent spontaneous abortion (RSA). miRNAs have essential functions in the proliferation and apoptosis of decidual tissues. However, the miRNAs involved in regulating oxidative stress in hDMSCs remain unclear. Methods Decidual tissues and hDMSCs were collected from patients with RSA and early pregnancy miscarriages. We assessed the antioxidant capacity of hDMSCs in both groups by detecting relevant indicators. Furthermore, differentially expressed miRNAs in hDMSCs were analyzed through miRNA sequencing. We evaluated the interaction between hsa-miR-532-3p and KEAP1 using a luciferase reporter assay. A mouse model of RSA was constructed for confirmation. Finally, we analyzed the correlations between serum hsa-miR-532-3p levels and the clinical features of pregnant women with RSA. Results miRNA sequencing revealed 44 miRNAs whose expression was downregulated and 9 miRNAs whose expression was upregulated in hDMSCs from the RSA group compared with those from the control group. The overexpression of hsa-miR-532-3p led to a significantly increased antioxidant capacity in hDMSCs. The knockdown or overexpression of hsa-miR-532-3p led to the upregulation or downregulation of KEAP1 expression, respectively. In a mouse model, the overexpression of hsa-miR-532-3p reduced embryo absorption rates in RSA mice, decreased KEAP1 expression levels in decidual tissues, and concurrently enhanced the resistance to oxidative stress. Furthermore, in patients diagnosed with RSA, serum hsa-miR-532-3p levels were significantly and negatively correlated with the gestational age. Conclusions Our study revealed a lower expression level of hsa-miR-532-3p in the hDMSCs of patients with RSA. Moreover, hsa-miR-532-3p protects hDMSCs from oxidative stress by targeting the Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (KEAP1/NRF2) pathway. Hsa-miR-532-3p is closely related to gestational age and has good predictive value for identifying RSA.

BackgroundCervical squamous cell carcinoma (CESC) constitutes a substantial global health burden, especially in resource-limited regions. The identification of reliable biomarkers is critical for developing a clinically applicable nomogram to predict survival outcomes and evaluate immune infiltration in CESC patients.MethodsThis study integrated RNA-seq data from GEO and TCGA databases to identify key genes associated with CESC through differential expression analysis and machine learning techniques. Prognostic models were constructed and validated, with additional analyses exploring immune cell infiltration and gene function via GSEA and clinical correlation. Finally, key genes were validated via qRT-PCR in CESC tissues.ResultsA total of 112 differentially expressed genes (DEGs) were identified through differential analysis of the GEO and TCGA datasets. EFNA1, CXCL8, and PPP1R14A emerged as prognostic biomarkers for CESC, showing significant associations with survival, tumor stage, and immune infiltration. EFNA1 may drive tumor progression via the MAPK signaling pathway, CXCL8 could influence immune evasion through NOD-like receptor signaling, and PPP1R14A may contribute to tumor invasion by modulating extracellular matrix remodeling. A nomogram integrating these genes demonstrated high predictive accuracy for overall survival (AUC>0.75) and calibration plots. Decision curve analysis (DCA) was performed to assess the nomogram’s clinical utility and net benefit for application in clinical practice. Additionally, it was validated by qRT-PCR, showing elevated expression in tumors versus normal tissues (P<0.05).ConclusionEFNA1, CXCL8, and PPP1R14A are promising biomarkers for CESC prognosis and immune regulation. The nomogram model provides a practical tool for personalized survival prediction, enhancing clinical decision-making for immunotherapy and risk stratification.

Background Preeclampsia (PE), a hypertensive pregnancy disorder, remains a leading cause of maternal and perinatal morbidity and mortality. Mitochondria-related placental metabolic dysfunction is implicated in PE, but its mechanistic role is unclear. This study aimed to identify mitochondria-related genes (MRGs) and their possible regulatory mechanisms in PE. Methods Differentially expressed mitochondria-related genes (MRGs) of PE were identified from Gene Expression Omnibus (GEO) dataset GSE114691 and GSE190971. LASSO regression analysis was used to screen key MRGs. Datasets GSE75010 and GSE25906 were used to validate the efficiency of the MRGs predictive model via receiver operating characteristic (ROC) curve analysis. Gene set enrichment analysis (GSEA) was conducted to verify underlying biological pathways in PE. Furthermore, we investigated the correlation analysis of MRGs and immune cell infiltration, as well as the association between the MRGs and clinical features. Single-cell sequencing analysis and immunofluorescence staining were used to verify the expression of critical gene in the placenta. Results Five hub MRGs (MOCS1, CYP11A1, GATM, SFXN3, and BCL2L11) showed high diagnostic accuracy for PE and correlated with immune cell infiltration. CYP11A1 was further associated with Hemolysis, Elevated Liver enzymes, Low platelets (HELLP) syndrome and predominantly expressed in extravillous trophoblasts, with upregulated expression in PE placenta. Conclusion The interaction between MRGs with the immune microenvironment might be vital in the development of PE. Among 5 hub MRGs, CYP11A1 might be a potential biomarker of HELLP syndrome. These findings provide novel insights into the underlying pathophysiology of PE and the discovery of new therapeutic targets.

ObjectivesTo develop and validate a nomogram to predict severe postpartum hemorrhage following cesarean delivery.MethodsThis is a two-center retrospective cohort study. Cesarean delivery patients from the First Affiliate Hospital of Jinan University were divided into a development cohort (n = 11 137) and an internal validation cohort (n = 4739). Cesarean delivery patients from the Dongguan Maternal and Child Health Care Hospital (n = 13 775) were enrolled in the external validation cohort. The nomogram was based on independent risk factors for severe postpartum hemorrhage obtained by multivariate logistic regression. We evaluated the discrimination and calibration of the nomogram in the development and validation cohorts.ResultsThe nomogram used data including previous cesarean delivery, pre-pregnancy weight, preterm birth, placenta previa, placenta accreta spectrum disorders, placental abruption, and mode of anesthesia. The area under the curves of the nomogram in the internal and external validation cohorts were 0.922 (95% confidence interval [CI] 0.897-0.947) and 0.813 (95% CI 0.785-0.841), respectively. Consistency between the predicted and actual probabilities was observed in both validation cohorts.ConclusionsThe nomogram displayed good calibration and discrimination and can be used for screening in clinical practice to enable clinicians to intervene appropriately.

Patients with early-onset preeclampsia (EOPE) have a most severe disease state. a2-macroglobulin (A2M) play a crucial role in the pathogenesis of EOPE, but its molecular basis and therapeutic potential remain unclear. This study aimed to elucidate the mechanisms of A2M in EOPE progression and explore the potential of A2M in the treatment of EOPE. A2M-Low Density Lipoprotein Receptor-Related Protein 1 (LRP1) blocker Receptor-associated protein (RAP) were utilized to alleviate the disease symptom of lipopolysaccharide (LPS) induced preeclampsia rat model. RNA-seq data sourced from public databases and morphological experiments were utilized to examine the relationship between the main fate of smooth muscle cell (SMC) during uterine spiral artery remodeling (SPA-REM) and A2M. Proteomic sequencing analysis of A2M overexpression rat placenta was used to identify the underlying mechanism. Further, LC-MS/MS analysis combined with Co-immunoprecipitation (Co-IP) was used to examine the interacting between A2M and underlying mechanism. Single-cell analysis and morphological experimental results suggest that SMC phenotype switching disorder is the main fate of SMC in the pathological of SPA-REM disorder, and A2M has a causal relationship with this process. Proteomic sequencing data suggest that A2M participates in this process through the RhoA-GTPase pathway, further experimental data provide evidences that A2M can directly upregulate RhoA-GTPase. Cytological and explant experiments suggest that RAP has better efficacy than A2M knockdown AAV vector, finally the efficacy of RAP was verified in the rat model of preeclampsia. SMC A2M promotes the progression of preeclampsia by directly upregulating RhoA-GTPase. Our findings also reveal that A2M serve as a potential target for EOPE and provide a preliminary therapy for inhibit the combination of A2M-LRP1.

Preeclampsia (PE) is a hypertensive disorder of severe pregnancy complication characterized by placental dysfunction and systemic inflammation. Resveratrol (RES), a natural polyphenol, has been shown to exert anti-inflammatory effects partly through the activation of SIRT1. NLRP3 inflammasome-mediated pyroptosis plays a crucial role in placental inflammation. This study aims to investigate the role of RES in regulating trophoblast pyroptosis through SIRT1 activation in PE. Placental tissues from PE patients and normal pregnancies were analyzed for SIRT1 and pyroptosis markers. A lipopolysaccharide (LPS)-induced PE mouse model and HTR-8/SVneo trophoblasts model were used to examine for pyroptosis following RES treatment. Placental tissues from PE patients exhibited significantly reduced SIRT1 expression and elevated pyroptosis markers (NLRP3, Caspase-1) compared to normal pregnancies. In a LPS-induced PE mouse model, RES treatment ameliorated pregnancy outcomes by reducing blood pressure, proteinuria, and improving renal morphology. RES also enhanced fetal and placental development, as evidenced by decreased embryo resorption rates, increased fetal weight, and improved spiral artery remodeling. Mechanistically, RES upregulated SIRT1 expression and suppressed pyroptosis-related proteins (NLRP3, Caspase-1, GSDMD, ASC) in placental tissues of PE mice. In vitro, RES attenuated LPS-induced trophoblast dysfunction by enhancing proliferation, migration, and invasion in HTR-8/SVneo cells. This was accompanied by SIRT1-mediated suppression of pyroptosis and reduced secretion of inflammatory cytokines (IL-18, IL-1β). These findings demonstrate that RES activates SIRT1 to inhibit trophoblast pyroptosis, thereby improving placental function and pregnancy outcomes in PE. This study highlights RES as a potential therapeutic agent for PE by modulating SIRT1-mediated pyroptosis pathways.

BACKGROUND: Preeclampsia, a severe pregnancy complication with an incompletely deciphered cause, is strongly associated with hyperlipidemia. Our previous studies demonstrated that FTL (ferritin light chain) expression was diminished in preeclampsia placentas and that FTL downregulation inhibited trophoblast invasiveness and migration while promoting apoptosis, contributing to preeclampsia development. However, the potential interplay between hyperlipidemia and FTL in the pathogenesis of preeclampsia, as well as the regulatory mechanism involved, remains to be elucidated. METHODS: We conducted Spearman correlation analysis, used a high-fat diet-fed mice model, cell culture, and molecular biology assays, including immunohistochemistry, chromatin immunoprecipitation, and dual-luciferase reporter gene assays, to explore the impact of hyperlipidemia on the development of preeclampsia and to elucidate the molecular mechanisms involved. RESULTS: Pregnant women with preeclampsia presented elevated serum total cholesterol, triglycerides, and low-density lipoprotein, with reduced high-density lipoprotein. Similarly, high-fat diet-fed mice exhibited dyslipidemia and preeclampsia-like characteristics. FTL expression was reduced in the placentas of patients with preeclampsia and high-fat diet-fed pregnant mice. In vitro, palmitic acid treatment reduced FTL expression, increased oxidative stress, and impaired trophoblast migration and invasion. GATA3 (GATA binding protein 3) was predicted to be an upstream transcription factor for FTL, with its knockdown reducing and its overexpression increasing FTL levels. Further analysis indicated that palmitic acid suppressed FTL expression by inhibiting GATA3 nuclear translocation and that AMPK (AMP-activated protein kinase) activation rescued FTL expression and restored trophoblast function. CONCLUSIONS: This study revealed that high lipid levels contribute to preeclampsia by downregulating FTL through the AMPK-GATA3 pathway, highlighting potential therapeutic targets for preeclampsia management.