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Background <p>Fetal growth restriction (FGR) is&#xa0;associated with perinatal complications and potential&#xa0;neurodevelopmental risks, yet mechanistic understanding of metabolic dysregulation remains incomplete. We investigated amniotic fluid metabolites as&#xa0;potential functional biomarkers of fetal-placental dysfunction and explored&#xa0;the possibility of folic acid-mediated epigenetic remediation of metabolic imbalances in FGR.</p> Results <p>In FGR amniotic fluid, hypoxanthine was significantly upregulated, valproic acid (VPA) was significantly&#xa0;downregulated, and arginine/proline metabolism pathways were markedly enriched. Folic acid intervention significantly improved fetal growth parameters (crown–rump length, body weight, and placental weight; all <i>P</i> &lt; 0.001). Compensatory labyrinth zone (Lb) hyperplasia was observed in FGR placenta, with a 40% increase in Lb/Jz ratio, while folic acid supplementation reduced Lb proportion by 10% and&#xa0;appeared to restore placental architecture. Epigenetically, folic acid supplementation suppressed histone deacetylases1 (HDAC1) expression, elevated H3K9ac levels and enhanced trophoblast proliferation.</p> Conclusions <p>Our research suggests that dysregulation of the VPA-hypoxanthine axis may serve as a hallmark of FGR-associated metabolic stress. Folic acid may&#xa0;exerts&#xa0;potential dual therapeutic effects by correcting placental architecture through Lb normalization and initiating epigenetic reprogramming via HDAC1 inhibition and acetylation at lysine 9 of histone H3 (H3K9ac). These findings indicate that folate metabolism could play a regulatory role in placental gene transcription and fetal growth trajectories.</p>

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Folic acid ameliorates placental structure and function in fetal growth restriction via epigenetic modifications

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月24日

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  • Juanmei Gao,
  • Yingya Lou,
  • Weiwu He,
  • Kaixing Xu,
  • Xin Zhan,
  • Jinyi Tong,
  • Hongbo Zhai

摘要

Background

Fetal growth restriction (FGR) is associated with perinatal complications and potential neurodevelopmental risks, yet mechanistic understanding of metabolic dysregulation remains incomplete. We investigated amniotic fluid metabolites as potential functional biomarkers of fetal-placental dysfunction and explored the possibility of folic acid-mediated epigenetic remediation of metabolic imbalances in FGR.

Results

In FGR amniotic fluid, hypoxanthine was significantly upregulated, valproic acid (VPA) was significantly downregulated, and arginine/proline metabolism pathways were markedly enriched. Folic acid intervention significantly improved fetal growth parameters (crown–rump length, body weight, and placental weight; all P < 0.001). Compensatory labyrinth zone (Lb) hyperplasia was observed in FGR placenta, with a 40% increase in Lb/Jz ratio, while folic acid supplementation reduced Lb proportion by 10% and appeared to restore placental architecture. Epigenetically, folic acid supplementation suppressed histone deacetylases1 (HDAC1) expression, elevated H3K9ac levels and enhanced trophoblast proliferation.

Conclusions

Our research suggests that dysregulation of the VPA-hypoxanthine axis may serve as a hallmark of FGR-associated metabolic stress. Folic acid may exerts potential dual therapeutic effects by correcting placental architecture through Lb normalization and initiating epigenetic reprogramming via HDAC1 inhibition and acetylation at lysine 9 of histone H3 (H3K9ac). These findings indicate that folate metabolism could play a regulatory role in placental gene transcription and fetal growth trajectories.