Work

METTL3-mediated N6-methyladenosine modification of LEPR is critical for fetal growth restriction

Year: 2026

Type: article

Abstract: Fetal growth restriction (FGR) is one of the most common perinatal complications. The specific molecular mechanism remains undefined. N6-methyladenosine (m 6 A), the most common RNA modification in eukaryotes, is known to be associated with a variety of diseases. However, the relationships among METTL3, m 6 A and FGR have not been clearly reported. The expression of METTL3, downstream target-leptin receptor (LEPR) and m 6 A modification level were compared between placentas of FGR and those of normal pregnancies. C57BL/6 pregnant mice were intraperitoneally injected with the METTL3-specific inhibitor STM2457 to analyze the effects of METTL3-associated m 6 A methylation. Changes downstream of METTL3 were determined by RNA sequencing. The regulatory relationships among METTL3, m 6 A, and LEPR were explored by cell migration assay, invasion assay, CCK8 assay, Western blotting and MeRIP‒qPCR. METTL3, LEPR and m 6 A modification were significantly decreased in the placenta of patients with FGR. After STM2457 treatment, adverse pregnancy outcomes and the FGR phenotype of fetal mice were observed. RNA-seq revealed that the downstream target of METTL3 was LEPR. The expression of LEPR was positively correlated with that of METTL3 via in vitro cellular mechanism experiments. The m 6 A modification level of LEPR was decreased when METTL3 was knocked down and increased when METTL3 was overexpressed. Furthermore, METTL3 and LEPR can separately or collectively promote the proliferation, migration and invasion of trophoblasts likely through m 6 A modification. Our study revealed that METTL3 regulated trophoblastic function likely through an m 6 A-LEPR-dependent mechanism in HTR8/SVneo cells and identified a potential biomarker panel for treatment prediction in FGR. • FGR is one of the most common perinatal complications and is associated with numerous short- and long-term health consequences. • The inhibition of METTL3 in vivo can result in an FGR phenotype in offspring. • The m 6 A modification of METTL3-mediated LEPR influences the biological function of trophoblasts. • METTL3 could be a potential therapeutic target in FGR.

Source: Placenta

DOI: 10.1016/j.placenta.2026.01.013