METTL3 promotes trophoblast ferroptosis in preeclampsia by stabilizing the ACSL4 m 6 A modification

作者全名：Wang, Yang; Zhang, Gang; Gao, Yan; Zhang, Xuemei; Qi, Hongbo

作者地址：[Wang, Yang; Zhang, Xuemei; Qi, Hongbo] Chongqing Med Univ, Affiliated Hosp 1, Dept Obstet, Chongqing 400016, Peoples R China; [Wang, Yang; Zhang, Xuemei; Qi, Hongbo] Chongqing Med Univ, Chongqing Key Labtory Maternal & Fetal Med, Chongqing 400016, Peoples R China; [Wang, Yang; Zhang, Gang; Gao, Yan] Chengdu Med Coll, Sichuan Prov Hosp Women & Children, Dept Obstet, Affiliated Women & Childrens Hosp, Chengdu 610041, Sichuan, Peoples R China; [Qi, Hongbo] Chongqing Med Univ, Dept Obstet & Gynecol, Women & Childrens Hosp, Chongqing 401147, Peoples R China

通信作者：Zhang, XM; Qi, HB (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Obstet, Chongqing 400016, Peoples R China.; Zhang, XM; Qi, HB (通讯作者)，Chongqing Med Univ, Chongqing Key Labtory Maternal & Fetal Med, Chongqing 400016, Peoples R China.; Qi, HB (通讯作者)，Chongqing Med Univ, Dept Obstet & Gynecol, Women & Childrens Hosp, Chongqing 401147, Peoples R China.

来源：EXPERIMENTAL CELL RESEARCH

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001218353500001

JCR分区：Q2

影响因子：3.3

年份：2024

卷号：437

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：N 6-methyladenosine; Methyltransferase-like 3; Ferroptosis; Trophoblasts; Preeclampsia

摘要：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 hypoxiastimulated 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.

基金机构：National Natural Science Foundation of China [8217061884, U21A20346, 82171662]; Science and Technology Research Project of Education Committee of Chongqing City [KJQN202200475]; National Key Research and Development Program of China [2023YFC2705900]; Sichuan Science and Technology Program [2023YFQ0005]

基金资助正文：This work was supported by National Natural Science Foundation of China (8217061884) , the Science and Technology Research Project of Education Committee of Chongqing City (KJQN202200475) , Joint Funds of the National Natural Science Foundation of China (No. U21A20346) , General Program of National Natural Science Foundation of China (No. 82171662) , National Key Research and Development Program of China (2023YFC2705900) , and Sichuan Science and Technology Program (Grant number 2023YFQ0005).