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 mA in cells, whereas silencing METTL3 partially reversed this change. Silencing METTL3 resulted in a decrease in mA 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 preeclampsia symptoms by catalyzing the mA modification of ACSL4 mRNA.

中文翻译：

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METTL3 通过稳定 ACSL4 m6A 修饰促进先兆子痫的滋养层铁死亡

本研究旨在探讨甲基转移酶样 3 (METTL3) 调节铁死亡在滋养层介导的先兆子痫发病机制中的作用。使用 qPCR 和蛋白质印迹技术测量临床胎盘组织和滋养层中 METTL3 和酰基辅酶 A 合成酶长链家族成员 4 (ACSL4) 的表达。 METTL3 对先兆子痫症状的影响也在大鼠模型中得到了验证。 METTL3 和 ACSL4 在先兆子痫患者的胎盘组织和缺氧诱导的滋养层中表达上调。 METTL3沉默增加了缺氧条件下培养的滋养层细胞的迁移和侵袭。 METTL3 的敲低增加了细胞活力并抑制了缺氧刺激的滋养层细胞中的铁死亡。缺氧增加了细胞中的 mA 水平，而沉默 METTL3 则部分逆转了这种变化。沉默 METTL3 会导致 ACSL4 mRNA 的 mA 修饰减少，从而导致 ACSL4 mRNA 稳定性降低。 ACSL4 上调部分逆转了 METTL3 沉默对缺氧刺激的滋养层细胞活力、迁移、侵袭和铁死亡的影响。在先兆子痫大鼠中抑制 METTL3 可降低血压、尿蛋白水平、胎儿存活率和 ACSL4 介导的铁死亡。 METTL3 通过催化 ACSL4 mRNA 的 m6A 修饰来升高铁死亡，从而抑制滋养细胞的迁移和侵袭以及先兆子痫症状。