2. Academic Validation
  3. METTL3 promotes trophoblast ferroptosis in preeclampsia by stabilizing the ACSL4 m6A modification

METTL3 promotes trophoblast ferroptosis in preeclampsia by stabilizing the ACSL4 m6A modification

  • Exp Cell Res. 2024 Mar 8:113990. doi: 10.1016/j.yexcr.2024.113990.
Yang Wang 1,  Gang Zhang 2,  Yan Gao 2,  Xuemei Zhang 3,  Hongbo Qi 4
Affiliations

Affiliations

  • 1 The Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Chongqing Key Labtory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China; Department of Obstetrics, Sichuan Provincial Maternity and Child Health Care Hospital, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu 610041, Sichuan Province, China.
  • 2 Department of Obstetrics, Sichuan Provincial Maternity and Child Health Care Hospital, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu 610041, Sichuan Province, China.
  • 3 The Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Chongqing Key Labtory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China. Electronic address: zhangxuemei@hospital.cqmu.edu.cn.
  • 4 The Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Chongqing Key Labtory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China; Women and Children's Hospital of Chongqing Medical University, Chongqing 401147, China. Electronic address: yuggy811@126.com.
PMID: 38462207 DOI: 10.1016/j.yexcr.2024.113990
Abstract

This study aims to explore the role of methyltransferase-like 3 (METTL3) modulation of Ferroptosis in the pathogenesis of trophoblast-mediated preeclampsia. The expression of METTL3 and acyl-CoA synthetase long chain family member 4 (ACSL4) was measured in clinical placental tissues and trophoblasts using qPCR and Western blot techniques. The effects of METTL3 on the symptoms of preeclampsia were also validated in rat models. METTL3 and ACSL4 were upregulated in placental tissues from patients with preeclampsia and in hypoxia-induced trophoblasts. METTL3 silencing increased the migration and invasion of trophoblasts cultured under hypoxic conditions. Knockdown of METTL3 increased cell viability and suppressed Ferroptosis in hypoxia-stimulated trophoblasts. Hypoxia increased the level of m6A in cells, whereas silencing METTL3 partially reversed this change. Silencing METTL3 resulted in a decrease in m6A modification of ACSL4 mRNA, which led to a reduction in ACSL4 mRNA stability. ACSL4 upregulation partially reversed the effects of METTL3 silencing on cell viability, migration, invasion, and Ferroptosis in hypoxia-stimulated trophoblasts. Inhibition of METTL3 in preeclampsia rats decreased blood pressure, urine protein levels, fetal survival rate, and ACSL4-mediated Ferroptosis. METTL3 elevates Ferroptosis to inhibit the migration and invasion of trophoblasts and in vivo preeclampsia symptoms by catalyzing the m6A modification of ACSL4 mRNA.

Keywords

Ferroptosis; Methyltransferase-like 3; N(6)-methyladenosine; Preeclampsia; Trophoblasts.

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