Dunjin Chen

Placenta defects are one of the major causes of miscarriages, yet the underlying mechanisms remain poorly understood. We demonstrate that trophoblast-specific depletion of the acetyltransferase Kat5 , or introduction of acetylation-defective mutants Kat5-Q377E G380E and Kat5-Y47A , induces severe chromosomal instability (CIN) during trophoblast cells division, leading to embryonic lethality. Moreover, mutation of a key lysine acetyltransferase 5 (KAT5) substrate, H2A.Z, via the introduction of H2az1-K5R K8R K12R K14R (which prevents H2A.Z acetylation), phenocopies the effects of KAT5 loss. Integrated RNA sequencing and CUT&Tag in mouse trophoblast stem cells reveal that KAT5, through H2A.Z acetylation, regulates transcription of key mitotic genes ( Aurka , Aurkb , and Cenpa ). We extend our finding to human trophoblast stem cells, demonstrating a conserved role for KAT5 in preventing CIN. Clinical analysis of placental villi from recurrent pregnancy loss patients with copy number variations revealed reduced expression of KAT5 and acetylated H2A.Z. This study demonstrates that the conserved KAT5–H2A.Z acetylation pathway safeguards chromosomal stability in trophoblast cells, supporting placenta development and successful pregnancy.

Preeclampsia (PE) is a placenta-driven hypertensive disorder characterized by oxidative stress, mitochondrial dysfunction, and abnormal autophagy. However, how these stress-response programs are coordinated at the post-transcriptional level remains incompletely understood. We integrated transcriptomic, proteomic, and untargeted metabolomic profiling of placentas from PE patients and normotensive controls, followed by validation in an independent clinical cohort. Mechanistic roles were interrogated using hypoxia-treated HTR-8/SVneo trophoblasts and an L-NAME-induced PE-like mouse model. Autophagy dynamics were assessed using dual-fluorescent autophagic flux reporters, transmission electron microscopy, and molecular markers. Multi-omics analyses converged on oxidative stress-related pathways, oxidative phosphorylation, and autophagy. The m6A reader HNRNPC was selectively upregulated at the protein level in PE placentas and positively correlated with the autophagy-related SNARE protein SEC22B. Clinically, PE placentas exhibited elevated global m6A methylation, increased HNRNPC and SEC22B expression, enhanced autophagic activity, and excessive oxidative stress. In trophoblasts, hypoxia induced ROS and autophagy, while HNRNPC overexpression further amplified intracellular and mitochondrial ROS, enhanced autophagic flux, and promoted apoptosis. In vivo, placental overexpression of HNRNPC aggravated hypertension, proteinuria, placental structural damage, oxidative stress, and autophagy dysregulation in PE-like mice. Our findings implicate a potential HNRNPC-SEC22B-autophagy regulatory network that amplifies placental stress maladaptation in preeclampsia. This study links epitranscriptomic remodeling to redox and autophagy dysregulation, suggesting HNRNPC as a potential mechanistic hub and therapeutic target in PE.

Pathogenic viruses threaten fetal development by achieving vertical transmission and instigating placental immunopathology, while the pathobiological mechanisms and effective therapeutics remain critical gaps. Here, we reveal cyclophilin A (CypA) as a crucial host factor necessary for Zika virus (ZIKV) replication in human placental trophoblasts, acting independently of its canonical functions. ZIKV infection recruits CypA into the viral replication organelle and reconfigures its interactome, thereby subverting host RNA decay machinery and stress granule-mediated antiviral surveillance. Both genetic ablation of CypA and its pharmacological inhibition with clinically approved drug ciclosporin A (CsA) restrict ZIKV transplacental transmission and corresponding placental and fetal pathologies. Beyond its anti-ZIKV potency, CsA concurrently counteracts pathological type I interferon signaling by targeting the JAK1-STAT1/2 pathway, broadly ameliorating pregnancy-specific interferonopathies driven by viral infection or endogenous double-stranded RNA stress. Our findings elucidate CypA-governed ZIKV pathogenesis and license CsA as a promising dual-action therapeutic to counteract congenital viral infections.

Objective: To investigate whether prophylactic tranexamic acid reduces the incidence of postpartum haemorrhage in women with placenta praevia compared with placebo. Design: Randomised, double blind, placebo controlled, phase 3 study. Setting: 24 maternity units across China between July 2023 and March 2025. Participants: 1732 women with placenta praevia undergoing caesarean delivery. Interventions: Participants were randomly (1:1) assigned to receive prophylactic oxytocin and either tranexamic acid (1 g in 10 mL) or placebo (10 mL normal saline) diluted in 40 mL normal saline intravenously over 10 minutes, initiated within five minutes of umbilical cord clamping. Main outcome measures: The primary outcome was postpartum haemorrhage, defined as calculated estimated blood loss ≥1000 mL or as red cell transfusion within two days after delivery. Serious adverse events included thromboembolic events, seizures, acute kidney or liver injury, and maternal death. Results: Of 1732 women with placenta praevia who were randomised, 38 were excluded because they withdrew consent or were determined to be ineligible after randomisation. Primary outcome data were available for 99.8% (1691/1694) of the remaining women. Placenta accreta spectrum was diagnosed in 303 participants (17.9%). The primary outcome occurred in 29.7% (251/845) of the tranexamic acid group and 35.1% (297/846) of the placebo group (relative risk 0.85, 95.2% confidence interval (CI) 0.75 to 0.96; P=0.01). The rates of serious adverse events were similar between the tranexamic acid group and placebo group (0.5% (4 of 837) v 0.5% (4 of 845); relative risk 1.01, 95% CI 0.25 to 4.00). Conclusions: In women with placenta praevia who underwent caesarean delivery and received prophylactic oxytocin, treatment with tranexamic acid resulted in a statistically significant yet modest reduction in the incidence of postpartum haemorrhage, with no signal of increased serious adverse events. Trial registration: ClinicalTrials.gov NCT05811676 .

Objective: To address the critical unmet need in managing unexplained recurrent pregnancy loss (URPL), where current empiric therapies exhibit limited efficacy, by leveraging patient-derived organoids (PDOs) for personalized therapeutic discovery. This single-case report serves as a proof-of-concept application of PDO-guided precision therapy in URPL. Methods: A 29-year-old woman who experienced six consecutive pregnancy losses underwent endometrial PDO-based drug testing. Organoids and stromal cells were cultured from proliferative-phase endometrial biopsies, and growth responses were subsequently quantified using RNA-seq and functional assays. Results: Histological examination of the endometrium revealed increased fibrosis alongside reduced stromal cell and CD3+ T-cell infiltration at the maternal–fetal interface. Initial observations of the PDOs indicated that epithelial growth was delayed. A synergistic triple-therapy regimen (aspirin + low-dose heparin + almuabumab) was identified as a candidate for restoring uterine homeostasis. Combination therapy achieved an ongoing pregnancy. Following conservative management of intrahepatic cholestasis and preeclampsia, a cesarean delivery was performed at 34 ⁺¹ weeks, resulting in the birth of a healthy neonate. Conclusion: This study pioneered the use of PDOs as an innovative therapeutic model for URPL, targeting immune-thrombotic dysregulation and enabling precision therapy. These findings establish a precision medicine paradigm that integrates organoid pharmacology with dynamic pregnancy surveillance for refractory cases of URPL. However, these data are derived from a single patient and should thus be interpreted with caution, warranting confirmation in larger, prospective cohorts.

BACKGROUND: The sFlt-1 (soluble fms-like tyrosine kinase 1) and PlGF (placental growth factor) ratio holds significant value in the early identification of preeclampsia and risk stratification. However, its application within the Chinese population remains under-researched. This study evaluates the predictive performance of the sFlt-1/PlGF ratio in hospitalized Chinese patients with hypertensive disorders of pregnancy. METHODS: This prospective single-center cohort study (December 2023–June 2024) enrolled East Asian women aged ≥18 years with singleton pregnancies (23 weeks to 36 weeks and 6 days of gestation) and signs or symptoms of hypertensive disorders of pregnancy. A serum sFlt-1/PlGF level of 38 was selected as the critical value to differentiate risk levels. Maternal outcomes and fetal parameters were assessed within 2 weeks post-enrollment and statistically analyzed. RESULTS: The study included 132 hospitalized patients with hypertensive disorders of pregnancy, among whom 44 (33.3%) had an sFlt-1/PlGF ratio ≥38. The interval to delivery detected in the high-ratio group was significantly shorter (0.8 weeks compared with 4 weeks; P P <0.001). The sFlt-1/PlGF ≥38 had an area under the curve of 0.88 for predicting delivery within 2 weeks. This indicator also demonstrated good negative predictive performance in excluding maternal-fetal adverse outcomes (negative predictive values: severe preeclampsia, 0.93; severe small for gestational age, 0.93). CONCLUSIONS: The sFlt-1/PlGF ratio demonstrates strong predictive value for short-term delivery in hospitalized hypertensive disorders of pregnancy patients in China. Its high negative predictive value is particularly useful in excluding the risk of maternal-fetal adverse outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov/ Unique identifier: NCT06383858.

Posterior reversible encephalopathy syndrome (PRES) in pregnancy, triggered by obstetric conditions, is a neuroradiological syndrome and a critical materna

Early‐onset preeclampsia (EOPE) is associated with excessive apoptosis and inflammation, but the mechanistic link between these processes remains enigma. Here, we report elevated circulating pro‐apoptotic proteins in EOPE patients at early pregnancy, along with concurrent CASP3 activation and GSDME cleavage in EOPE placentas. Using multiple trophoblast cell lines, we demonstrate that trophoblast cells, which highly express GSDME, undergo a shift from apoptosis to CASP3‐dependent pyroptosis, driving inflammation. Notably, pyroptotic trophoblasts further induce pro‐inflammatory macrophage polarization within placental villi organoids, establishing a feedback loop that amplifies both trophoblast pyroptosis and inflammatory responses in trophoblast organoids‐macrophage assembloids. In vivo, CASP3‐GSDME‐mediated trophoblast pyroptosis contributes to systemic inflammation in wild‐type pregnant mice but not in Gsdme ^−/− mice. Screening of EOPE prevention drugs reveals Vitamin D as a suppressor of GSDME activation and pyroptosis in trophoblast cells. Together, our findings establish CASP3–GSDME–mediated pyroptosis as a mechanistic link between apoptosis and inflammation in EOPE.