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

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

  • J Adv Res. 2026 Mar 9:S2090-1232(26)00224-9. doi: 10.1016/j.jare.2026.03.005.
Zihao Huang 1,  Shijian Zhou 1,  Zhijuan Cui 1,  Jinfeng Li 1,  Liudan Liu 1,  Xuexun Feng 1,  Hongxuan Ye 1,  Kaidi Ma 1,  Shuangbo Huang 1,  Quanhang Xiang 2,  Wei Shi 3,  Jinping Deng 1,  Chengquan Tan 4
Affiliations

Affiliations

  • 1 Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China.
  • 2 Department of Shenzhen Institute of Respiratory Diseases, the Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518000, China.
  • 3 Department of Obstetrics and Gynecology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518000, China.
  • 4 Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Animal Nutrition Control, and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China. Electronic address: [email protected].
PMID: 41812706 DOI: 10.1016/j.jare.2026.03.005
Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

Angiogenesis; Ferroptosis; Gestational diabetes mellitus; HAMP; Placenta.

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