WTAP regulates NCOA4-mediated ferroptosis via a YTHDF2-dependent mechanism in preeclampsia

TL;DR

This study shows that WTAP prevents ferroptosis in preeclampsia by controlling NCOA4 through m6A methylation and YTHDF2.

Contribution

The study reveals a novel m6A-dependent mechanism involving WTAP, YTHDF2, and NCOA4 in regulating ferroptosis during preeclampsia.

Findings

WTAP and m6A levels are reduced in preeclampsia placentas, linked to impaired trophoblast function.

WTAP promotes NCOA4 mRNA degradation via YTHDF2, reducing ferroptosis and oxidative stress.

Disrupting this pathway worsens preeclampsia symptoms in mice, which are partially reversed by Ferrostatin-1.

Abstract

Preeclampsia (PE) is a pregnancy-specific hypertensive disorder associated with placental dysfunction and oxidative stress. This study explored whether WTAP regulates ferroptosis in trophoblasts through m6A-dependent control of NCOA4 and YTHDF2.

WTAP expression and global m6A levels in PE placentas were examined by qRT-PCR, western blot, and immunohistochemistry, along with histopathological analysis. WTAP, NCOA4, and YTHDF2 expression were manipulated in HTR-8/SVneo trophoblasts using siRNAs or overexpression plasmids. Cell proliferation, migration, cell-cycle distribution, oxidative stress, and ferroptosis markers were evaluated. MeRIP-qPCR and RIP-qPCR were used to assess NCOA4 m6A methylation and YTHDF2 binding. A PE mouse model was established to assess in vivo effects and the potential rescue by Ferrostatin-1 (Fer-1).

WTAP expression and global m6A levels were reduced in PE placentas, accompanied by villous structural damage. Functionally, WTAP knockdown suppressed trophoblast proliferation and migration, induced G1 arrest, and enhanced oxidative stress, while WTAP overexpression had opposite effects. Mechanistically, WTAP promoted m6A methylation of NCOA4 mRNA and its YTHDF2-dependent degradation. In PE placentas, YTHDF2 was downregulated and NCOA4 upregulated, consistent with in vitro findings. NCOA4 overexpression impaired trophoblast function and increased ferroptosis, whereas silencing had protective effects. YTHDF2 knockdown and NCOA4 overexpression acted synergistically to exacerbate ferroptosis, both in trophoblasts and in a PE mouse model, leading to aggravated hypertension, proteinuria, and fetal growth restriction, which were partially reversed by Fer-1.

WTAP suppresses ferroptosis in PE by enhancing YTHDF2-dependent m6A methylation and degradation of NCOA4. Disruption of this pathway exacerbates oxidative stress, trophoblast dysfunction, and adverse pregnancy outcomes.

The online version contains supplementary material available at 10.1186/s13148-025-02004-w.

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