Preeclampsia is a leading contributor to increased maternal morbidity and mortality in the perinatal period. Increasing evidence demonstrates that ferroptosis is an essential mechanism for the pathogenesis of preeclampsia. Elabela is a novel small-molecule polypeptide, mainly expressed in embryonic and transplacental tissues, with an ability to promote cell proliferation and invasion. However, its specific regulatory mechanism in preeclampsia has not been completely elucidated. In this study, we first reveal an increased grade of ferroptosis accompanied by a downregulation of the expression of Elabela in preeclampsia placentas. We then confirm the presence of a ferroptosis phenotype in the placenta of the mouse PE-like model, and Elabela can reduce ferroptosis in the placenta and improve adverse pregnancy outcomes. Furthermore, we demonstrate that targeting Elabela alleviates the cellular dysfunction mediated by Erastin promoting increased lipid peroxidation in vitro. Subsequent mechanistic studies suggest that Elabela increases FTH1 levels by inhibiting the ferritinophagy pathway, and consequently chelates the intracellular labile iron pool and eventually arrests ferroptosis. In conclusion, Elabela deficiency exacerbates ferroptosis in the placenta, which is among the potential mechanisms in the pathogenesis of preeclampsia. Targeting the Elabela–ferritinophagy–ferroptosis signaling axis provides a new therapeutic intervention strategy to alleviate preeclampsia.

Preeclampsia (PE) is a pregnancy-specific disorder characterized by placental dysfunction, immune activation, and oxidative stress. Extrachromosomal circular DNA (eccDNA), a class of circular DNA fragments that exist outside the chromosomes, has been implicated in cancer, aging, and inflammation, but its role in PE remains poorly understood. EccDNA abundance was quantified in placental tissues from PE and control pregnancies and correlated with clinical parameters. Synthetic eccDNA was used to treat trophoblast cells in vitro. Functional assays, ferroptosis biomarkers, RNA sequencing, and STING pathway activation were assessed. STING knockdown and pharmacological inhibition were employed for validation. We confirmed abundant eccDNA in trophoblasts, enriched in nuclear heterochromatin, with significantly elevated levels in PE. Mechanistically, eccDNA acts as a potent activator of the STING signaling pathway, inducing downstream pro-inflammatory cytokines including IFN-β, IL-6, and TNF-α.RNA sequencing and biochemical assays further demonstrated that eccDNA also triggered ferroptosis. STING activation promoted lipid peroxide accumulation and impaired antioxidant defenses, exacerbating ferroptotic cell death. Inflammatory signaling synergized with ferroptosis to exacerbate oxidative stress and cell damage, ultimately leading to trophoblast dysfunction. Genetic silencing or pharmacological inhibition of STING effectively reversed both inflammatory and ferroptotic damage. Analysis of clinical samples revealed an upregulation of STING in trophoblasts derived from preeclamptic placentas, accompanied by enhanced ferroptosis. Our study identifies eccDNA as a key activator of the STING pathway, driving inflammation and ferroptosis in PE, contributing to trophoblast dysfunction. This dual pathological mechanism represents a potential etiological pathway in the onset of PE.

Rationale: Placental mesenchymal dysplasia (PMD) is a rare placental disorder that poses diagnostic challenges and is often misdiagnosed as a trophoblastic tumor. While PMD is associated with fetal growth restriction, intrauterine fetal death, and pregnancy-induced hypertension, it does not involve malignant trophoblastic disease. Accurate diagnosis is crucial for optimizing maternal and fetal outcomes. Patient concerns: A 30-year-old female, gravida 3, para 1, with an uncomplicated medical history, presented with early pregnancy bleeding, which was managed with oral progesterone. Ultrasound at 13 weeks showed normal fetal morphology but a honeycomb-like placental appearance. At 23 weeks, ultrasound revealed fetal growth restriction, thickening of the placenta, and abnormal umbilical artery flow. Magnetic resonance imaging at 32 weeks confirmed abnormal placental masses. Diagnoses: Ultrasound, magnetic resonance imaging, and genetic testing (noninvasive prenatal testing, amniocentesis, and chromosomal microarray analysis) confirmed normal karyotype and identified distinctive placental abnormalities. Histopathological examination revealed edematous villi, fibromuscular hyperplasia, and amyloid-like protein deposits, consistent with PMD. Interventions: Prenatal care included enoxaparin sodium and management of fetal distress at 32 weeks with a cesarean section. Magnesium sulfate and dexamethasone were administered for fetal protection. Outcomes: Both mother and infant were healthy postpartum. The infant had favorable Apgar scores, and the patient’s blood pressure was managed with antihypertensive therapy. Maternal β-human chorionic gonadotropin levels remained normal throughout the pregnancy and postpartum. Lessons: PMD is an exceptionally rare placental disorder with a low incidence. It often presents with atypical ultrasound findings and can easily be misdiagnosed as a trophoblastic tumor, leading to unnecessary interventions. Diagnosing PMD is challenging, particularly in the absence of specific clinical symptoms. Clinicians must enhance awareness of this rare condition, prioritize early and accurate diagnosis through advanced imaging and histopathology, and differentiate PMD from other placental pathologies to ensure appropriate management and improve maternal-fetal outcomes.

Preeclampsia (PE) is a pregnancy-specific syndrome driven by placental dysfunction, and premature placental senescence has increasingly been implicated in its pathogenesis. However, the upstream regulatory mechanisms remain poorly understood. Here, we found that placental SIRT1 expression was reduced in PE and was accompanied by senescence-associated features. In trophoblasts, SIRT1 knockdown enhanced senescence and senescence-associated secretory phenotype (SASP) release, while impairing proliferative capacity, migration, and invasion, whereas pharmacological activation of SIRT1 attenuated placental senescence and ameliorated PE-like manifestations in vivo . Mechanistically, iron chelation alleviated senescence, whereas senolytic intervention partially restored iron homeostasis, supporting a self-reinforcing interaction between iron dyshomeostasis and senescence. Collectively, these findings identify the SIRT1–p53 axis as an upstream regulator linking iron dyshomeostasis to placental senescence, support the existence of a ferro-aging-like pathogenic program in diseased placentas, and provide new insights into the molecular basis of placental dysfunction in PE.

Extrachromosomal circular deoxyribonucleic acids are increasingly recognized as dynamic genomic elements with potential regulatory functions, but their cha