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Elabela: Negative Regulation of Ferroptosis in Trophoblasts via the Ferritinophagy Pathway Implicated in the Pathogenesis of Preeclampsia

Preeclampsia is a leading contributor to increased maternal morbidity and mortality in the perinatal period. Increasing evidence demonstrates that ferroptosis is an essential mechanism for the pathogenesis of preeclampsia. Elabela is a novel small-molecule polypeptide, mainly expressed in embryonic...

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Autores principales: Yang, Huan, Zhang, Xuemei, Ding, Yubin, Xiong, Hui, Xiang, Shaojian, Wang, Yang, Li, Huanhuan, Liu, Zheng, He, Jie, Tao, Yuelan, Yang, Hongbing, Qi, Hongbo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9818811/
https://www.ncbi.nlm.nih.gov/pubmed/36611895
http://dx.doi.org/10.3390/cells12010099
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author Yang, Huan
Zhang, Xuemei
Ding, Yubin
Xiong, Hui
Xiang, Shaojian
Wang, Yang
Li, Huanhuan
Liu, Zheng
He, Jie
Tao, Yuelan
Yang, Hongbing
Qi, Hongbo
author_facet Yang, Huan
Zhang, Xuemei
Ding, Yubin
Xiong, Hui
Xiang, Shaojian
Wang, Yang
Li, Huanhuan
Liu, Zheng
He, Jie
Tao, Yuelan
Yang, Hongbing
Qi, Hongbo
author_sort Yang, Huan
collection PubMed
description Preeclampsia is a leading contributor to increased maternal morbidity and mortality in the perinatal period. Increasing evidence demonstrates that ferroptosis is an essential mechanism for the pathogenesis of preeclampsia. Elabela is a novel small-molecule polypeptide, mainly expressed in embryonic and transplacental tissues, with an ability to promote cell proliferation and invasion. However, its specific regulatory mechanism in preeclampsia has not been completely elucidated. In this study, we first reveal an increased grade of ferroptosis accompanied by a downregulation of the expression of Elabela in preeclampsia placentas. We then confirm the presence of a ferroptosis phenotype in the placenta of the mouse PE-like model, and Elabela can reduce ferroptosis in the placenta and improve adverse pregnancy outcomes. Furthermore, we demonstrate that targeting Elabela alleviates the cellular dysfunction mediated by Erastin promoting increased lipid peroxidation in vitro. Subsequent mechanistic studies suggest that Elabela increases FTH1 levels by inhibiting the ferritinophagy pathway, and consequently chelates the intracellular labile iron pool and eventually arrests ferroptosis. In conclusion, Elabela deficiency exacerbates ferroptosis in the placenta, which is among the potential mechanisms in the pathogenesis of preeclampsia. Targeting the Elabela–ferritinophagy–ferroptosis signaling axis provides a new therapeutic intervention strategy to alleviate preeclampsia.
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spelling pubmed-98188112023-01-07 Elabela: Negative Regulation of Ferroptosis in Trophoblasts via the Ferritinophagy Pathway Implicated in the Pathogenesis of Preeclampsia Yang, Huan Zhang, Xuemei Ding, Yubin Xiong, Hui Xiang, Shaojian Wang, Yang Li, Huanhuan Liu, Zheng He, Jie Tao, Yuelan Yang, Hongbing Qi, Hongbo Cells Article Preeclampsia is a leading contributor to increased maternal morbidity and mortality in the perinatal period. Increasing evidence demonstrates that ferroptosis is an essential mechanism for the pathogenesis of preeclampsia. Elabela is a novel small-molecule polypeptide, mainly expressed in embryonic and transplacental tissues, with an ability to promote cell proliferation and invasion. However, its specific regulatory mechanism in preeclampsia has not been completely elucidated. In this study, we first reveal an increased grade of ferroptosis accompanied by a downregulation of the expression of Elabela in preeclampsia placentas. We then confirm the presence of a ferroptosis phenotype in the placenta of the mouse PE-like model, and Elabela can reduce ferroptosis in the placenta and improve adverse pregnancy outcomes. Furthermore, we demonstrate that targeting Elabela alleviates the cellular dysfunction mediated by Erastin promoting increased lipid peroxidation in vitro. Subsequent mechanistic studies suggest that Elabela increases FTH1 levels by inhibiting the ferritinophagy pathway, and consequently chelates the intracellular labile iron pool and eventually arrests ferroptosis. In conclusion, Elabela deficiency exacerbates ferroptosis in the placenta, which is among the potential mechanisms in the pathogenesis of preeclampsia. Targeting the Elabela–ferritinophagy–ferroptosis signaling axis provides a new therapeutic intervention strategy to alleviate preeclampsia. MDPI 2022-12-26 /pmc/articles/PMC9818811/ /pubmed/36611895 http://dx.doi.org/10.3390/cells12010099 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yang, Huan
Zhang, Xuemei
Ding, Yubin
Xiong, Hui
Xiang, Shaojian
Wang, Yang
Li, Huanhuan
Liu, Zheng
He, Jie
Tao, Yuelan
Yang, Hongbing
Qi, Hongbo
Elabela: Negative Regulation of Ferroptosis in Trophoblasts via the Ferritinophagy Pathway Implicated in the Pathogenesis of Preeclampsia
title Elabela: Negative Regulation of Ferroptosis in Trophoblasts via the Ferritinophagy Pathway Implicated in the Pathogenesis of Preeclampsia
title_full Elabela: Negative Regulation of Ferroptosis in Trophoblasts via the Ferritinophagy Pathway Implicated in the Pathogenesis of Preeclampsia
title_fullStr Elabela: Negative Regulation of Ferroptosis in Trophoblasts via the Ferritinophagy Pathway Implicated in the Pathogenesis of Preeclampsia
title_full_unstemmed Elabela: Negative Regulation of Ferroptosis in Trophoblasts via the Ferritinophagy Pathway Implicated in the Pathogenesis of Preeclampsia
title_short Elabela: Negative Regulation of Ferroptosis in Trophoblasts via the Ferritinophagy Pathway Implicated in the Pathogenesis of Preeclampsia
title_sort elabela: negative regulation of ferroptosis in trophoblasts via the ferritinophagy pathway implicated in the pathogenesis of preeclampsia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9818811/
https://www.ncbi.nlm.nih.gov/pubmed/36611895
http://dx.doi.org/10.3390/cells12010099
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