Mechanisms of YAP1-mediated Trophoblast Ferroptosis in Recurrent Pregnancy Loss

Overview

Journal J Assist Reprod Genet

Publisher Springer

Specialties Genetics
Reproductive Medicine

Date 2024 Mar 25

PMID 38526774

Authors

Liping Chen

Fangfang Dai

Yanjie Huang

Jing Chen

Zhidian Li

Hua Liu

Yanxiang Cheng

Affiliations

Soon will be listed here.

Abstract

Purpose: The purpose of our study is to investigate the function of YAP1 in the trophoblast ferroptosis and maternal-fetal interface communication of RPL.

Methods: We collected 25 villous tissues and detected the expression of YAP1. Cell counting kit-8 assay, scratch wound-healing assay, and Matrigel invasion assay were performed to observe the proliferation, migration, and invasion of HTR-8/SVneo and JAR cells. Subsequently, measured the levels of reactive oxygen species (ROS), malondialdehyde (MDA), reduced glutathione (GSH), SLC7A11, SOD2, and GPX4. Ultimately, the use of ferroptosis activator (erastin) and inhibitor (Ferrostatin-1, fer-1) further confirmed the regulation by YAP1. In addition, established an in vitro-induced cell model to study the effect of YAP1 on the decidualization process. Finally, animal models were implemented for further confirmation.

Results: We found that YAP1 was downregulated in RPL patients. Overexpression of YAP1 could significantly enhance the proliferation, migration, and invasion of trophoblasts, and inhibit ferroptosis. Knocking down YAP1 exhibited the opposite effect. Rescue experiments have shown that YAP1 could upregulate the expression of SLC7A11 and GPX4, which are key molecules in the classic pathway of ferroptosis. In addition, the decidualization was impaired when hESCs were treated with conditioned medium of YAP1 knockdown trophoblasts. Moreover, we found that Yap1, Slc7a11, and Gpx4 were downregulated in the RPL mice, along with increased MDA and decreased GSH.

Conclusion: Downregulation of YAP1 induces ferroptosis, thereby damaging the trophoblast invasion processes, which also disturbs the communication at the maternal-fetal interface. Our study identified YAP1 as a potential key molecule in the pathogenesis of RPL.

Citing Articles

MLL1 promotes placental trophoblast ferroptosis and aggravates preeclampsia symptoms through epigenetic regulation of RBM15/TRIM72/ADAM9 axis.

Li L, He H, Zheng Z, Zhao X Biol Direct. 2024; 19(1):133.

PMID: 39709463 PMC: 11663353. DOI: 10.1186/s13062-024-00572-0.

Metabolomic analysis reveals potential role of immunometabolism dysregulation in recurrent pregnancy loss.

Ye X, Ma C, Guo W, Guo Y, Li D, Zhou S Front Endocrinol (Lausanne). 2024; 15:1476774.

PMID: 39444455 PMC: 11496058. DOI: 10.3389/fendo.2024.1476774.

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