HIF-2α / HILPDA promotes ferroptosis sensitivity in placenta trophoblast cells of early-onset preeclampsia

  • Placenta. 2025 Dec 15:174:126-137. doi: 10.1016/j.placenta.2025.12.009.
Qianghua Wang  1 ,  Nana Yang  2 ,  Huijuan Chen  1 ,  Biao Ding  2 ,  Chengli Dou  3 ,  Xuegu Wang  2 ,  Xingchen Pan  3 ,  Xiaojing Wang  4 ,  Xiang Li  5
Affiliations
  • 1. Laboratory of Department of Infectious Diseases, First Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, Anhui, China.
  • 2. Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, Anhui, China.
  • 3. Molecular Diagnosis Center, Anhui Province Key Laboratory of Clinical and Preclinical Research in Respiratory Disease, First Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, Anhui, China.
  • 4. Molecular Diagnosis Center, Anhui Province Key Laboratory of Clinical and Preclinical Research in Respiratory Disease, First Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, Anhui, China. Electronic address: [email protected].
  • 5. Molecular Diagnosis Center, Anhui Province Key Laboratory of Clinical and Preclinical Research in Respiratory Disease, First Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, Anhui, China. Electronic address: [email protected].
PMID: 41422655 DOI: 10.1016/j.placenta.2025.12.009
Abstract

Background: Early-onset preeclampsia (EOPE) is a severe pregnancy disorder characterized by placental dysfunction. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a key pathogenic mechanism in EOPE. This study investigated the role of the hypoxia-inducible factor-2α (HIF-2α) and its downstream target, Hypoxia-Inducible Lipid Droplet-Associated protein (HILPDA), in regulating Ferroptosis in EOPE placentas.

Methods: Placental tissues from EOPE patients and normotensive controls were analyzed for Ferroptosis markers (MDA, GSH, ACSL4, Ferroportin-1, GPX4) and HILPDA/HIF-2α expression. In vitro models employed HTR-8/SVneo trophoblasts and primary human trophoblasts. HILPDA was manipulated via siRNA knockdown or CRISPR-Cas9 knockout. HIF-2α was pharmacologically activated using agonists (HIF-2α agonist 2, AKB-6899). Erastin was used to induce Ferroptosis. Assessments included CCK-8 assays for viability, C11-BODIPY581/591 staining and flow cytometry for lipid peroxidation, MDA/GSH quantification for Ferroptosis levels, qRT-PCR and Western blotting for HILPDA/HIF-α expression.

Results: EOPE placentas exhibited significantly elevated Ferroptosis, with increased MDA, ACSL4, Ferroportin-1; decreased GSH, GPX4, and upregulated expression of both HILPDA and HIF-2α (but not HIF-1α) compared to controls. In vitro, HIF-2α activation triggered HILPDA expression and robust Ferroptosis (increased lipid peroxidation, MDA; decreased GSH; reduced viability) in trophoblasts. Crucially, HILPDA knockdown/knockout significantly attenuated Ferroptosis sensitivity and protected trophoblast viability against both Erastin and HIF-2α agonist-induced ferroptotic stress. HIF-2α-induced Ferroptosis was substantially rescued by HILPDA deficiency.

Conclusion: Our findings identify the HIF-2α/HILPDA axis as a critical regulator of trophoblast Ferroptosis in EOPE. HIF-2α, upregulated in EOPE placenta, transcriptionally induces HILPDA, which sensitizes trophoblasts to ferroptotic death. Targeting this signaling pathway represents a promising therapeutic strategy for mitigating placental dysfunction in EOPE.

Keywords
Ferroptosis; HILPDA; Hif-2α; Preeclampsia.
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