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Cited by 198Ferroptosis and cancer prognosisPregnancy and preeclampsia studiesReproductive System and Pregnancy

PLA2G6 guards placental trophoblasts against ferroptotic injury

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Beharier, Ofer, Tyurin, Vladimir A., Goff, Julie P., Guerrero-Santoro, Jennifer, Kajiwara, Kazuhiro, Chu, Tianjiao, Tyurina, Yulia Y., St Croix, Claudette M. +5 more·2020·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2009201117PMC PMC7959495
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Abstract

Significance: Placental dysfunction has been causally linked to major pregnancy complications that are implicated in maternal–fetal morbidity and mortality, but the mechanisms underlying placental dysfunction are largely unknown. The recently identified ferroptotic cell death is characterized by excessive accumulation of hydroperoxide phosphatidylethanolamines. While oxidative damage commonly defines placental dysfunction, the role of ferroptosis in this process is largely unknown. We found that preterm birth is associated with ferroptotic signals, and that inhibition of GPX4, which converts unstable lipid hydroperoxides to nontoxic lipid alcohols, causes ferroptotic injury in primary human trophoblasts and in mouse pregnancy. Importantly, we found that the phospholipase PLA2G6 mitigates trophoblast and placental ferroptosis. Together, we identified placental ferroptosis and established a role for PLA2G6 in attenuating ferroptosis.

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  • Each type of PLA2 has substrate-specific activity, and depending on the substrate, PLA2 can either promote or block ferroptosis.

    “Each type of PLA2 has a substrate-specific activity, and depending on the substrate, PLA2 can either promote or block ferroptosis (28–31).”

    From Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis (2024) · cites this paper as [30]

    The Discussion (page unavailable) says PLA2G6 metabolizes proferroptotic Hp-PE species and helps defend trophoblasts against ferroptosis. The Results (page unavailable) also show that PLA2G6 loss increases ferroptosis sensitivity. The paper does not establish that each type of PLA2 has substrate-specific activity or that PLA2 can promote ferroptosis depending on its substrate. (LLM, conf=0.86)

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References 90 · Cited by 198

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Authors
Beharier, O., Tyurin, V. A., Goff, J. P., Guerrero-Santoro, J., Kajiwara, K., Chu, T., Tyurina, Y. Y., St Croix, C. M., Wallace, C. T., Parry, S., Parks, W. T., Kagan, V. E., & Sadovsky, Y.
Affiliations
  • University of Pittsburgh (US)
  • Magee-Womens Research Institute, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA 15213;
  • Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15261;
  • University of Pennsylvania (US)
  • Mount Sinai Hospital (CA)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2020-10-21
Volume
117
Issue
44
Pages
27319-27328
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2009201117
PMC
PMC7959495
OpenAlex
W3094620150
Cited by
198
References
90
Citations by year
2026: 25 · 2025: 38 · 2024: 39 · 2023: 49 · 2022: 31 · 2021: 16
FWCI
13.53
Type
journal article
Language
en
Open access
Licence
www.pnas.org/site/aboutpnas/licenses.xhtml (vor, 182 d)
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD069316)
  • March of Dimes Foundation (N/A)
  • 25 Club of Magee-Womens Hospital (N/A)
  • Magee-Womens Research Institute Postdoctoral Fellowship (N/A)
  • Jikei University School of Medicine (N/A)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
  • Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
  • Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
Keywords
ferroptosis, PLA2G6, iPLA2β, trophoblast, placenta, GPX4, lipotoxicity, preterm birth, hypoxia/reoxygenation injury, placental insufficiency, lipid peroxidation
MeSH terms
Ferroptosis, Phospholipid Hydroperoxide Glutathione Peroxidase, Animals, Female, Glutathione Peroxidase, Humans, Iron, Lipid Peroxides, Phosphatidylethanolamines, Placenta, Pregnancy, Trophoblasts, Signal Transduction, Mice, Knockout, Premature Birth, Mice, Group VI Phospholipases A2

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