Ferroptosis as a mechanism of placenta dysfunction in inflammation-driven preeclampsia.

BACKGROUND

Preeclampsia (PE) is a hypertensive pregnancy syndrome with significant clinical and pathological diversity, linked to distinct etiological subclasses. One etiological subclass of PE, characterized by increased inflammation at the maternal-fetal interface (I-PE), is strongly associated with preterm birth and fetal growth restriction, though its specific pathophysiology remains poorly understood. Inflammatory signals can induce iron overload, leading to ferroptosis-a programmed cell death process. Dysregulation of systemic and placental iron metabolism has been described in PE when considered as a single clinical entity, but previous studies have not accounted for distinct underlying etiologies. This study investigates the role of ferroptosis signaling in placental dysfunction across different PE subclasses.

METHODS

Histological analysis assessed placental iron accumulation and ferritin protein expression. Placental gene expression was evaluated for ferroptosis-related genes (FRGs) using gene set enrichment analysis (GSEA) on placenta samples from healthy controls and three previously described PE subclasses. Digital cytometry estimated cell type-specific expression of FRGs across these subclasses.

RESULTS

Significant placenta iron accumulation and reduced ferritin expression were found exclusively in I-PE subclass. GSEA showed enrichment of FRGs across various functional categories, including regulators, markers, suppressors, and unclassified FRGs in the placentas from I-PE. Digital cytometry indicated disrupted FRG expression in trophoblasts and mesodermal stromal cells in these placentas, consistent with histologically observed iron accumulation.

CONCLUSION

Placental iron accumulation and disrupted ferroptosis signaling in I-PE subclass suggests a novel mechanism of placental dysfunction unique to this subclass. Further research is needed to explore how regulating ferroptosis could aid in managing I-PE.