DHA ameliorates GDM placental angiogenesis by regulating HAMP-mediated iron imbalance

• Glucose intolerance promotes placental ferroptosis and endothelial dysfunction. • DHA alleviates ferroptosis and improves angiogenesis via HAMP suppression. • PARP1 inhibits HAMP transcription by regulating histone acetylation. • DHA restores PARP1 function and corrects iron dysregulation in the placenta. • GDM patients and PGT sows show placental HAMP upregulation and poor angiogenesis. Iron metabolism imbalance is closely associated with gestational diabetes mellitus (GDM), but the underlying mechanisms of its contribution to placental endothelial dysfunction and effective interventions remain unclear. Pregnant mice and sow models with impaired glucose tolerance, along with placental samples from women with GDM, were used to investigate the effects of abnormal glucose metabolism on placental iron homeostasis and angiogenesis. In vitro, endothelial cells and mouse allantois were treated with high glucose and palmitic acid to mimic metabolic-induced vascular injury. The potential therapeutic role of docosahexaenoic acid (DHA) in reversing these placental impairments was further evaluated. We show that a ferroptosis-prone state in the placenta under glucose intolerance is linked to impaired angiogenesis and that DHA supplementation can alleviate endothelial ferroptosis and vascular dysfunction by down-regulating placental hepcidin (HAMP) expression. Mechanistically, DHA reverses the reduction in PARP1 binding to the promoter and the overexpression of SREBF2 induced by glucose intolerance, and restores the inhibitory effect of PARP1 on histone acetylation at the Hamp promoter, thereby reducing endothelial HAMP expression, promoting intracellular ferrous iron efflux and ultimately improving angiogenic capacity. These findings reveal the critical role of iron dysregulation in placental endothelial impairment during GDM progression and highlight the therapeutic potential of DHA in restoring placental iron homeostasis and angiogenesis via placental HAMP regulation.