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Metabolic control of feto–placental development and pregnancy outcomes

Nature Reviews Endocrinology volume 22, pages 153–165 (2026)Cite this article

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Abstract

The intricate processes of feto–placental development are regulated by both genetics and the nutritional environment. The placenta mediates nutrient transfer to the fetus and waste transfer to the maternal circulation to facilitate proper fetal cell fate specification. Disruptions in these fate-regulatory programmes can lead to maternal and fetal complications. We explore how metabolic–epigenetic mechanisms programme feto–placental development, discussing the roles of metabolic sensing mechanisms. This Review covers the roles of nutrient metabolite-dependent protein modifications, lipid signalling, steroid signalling and oxygen signalling in regulating particular phases and lineages of feto–placental development. Understanding these environmental–genetic interactions is crucial for elucidating the limits of developmental plasticity, the pathogenesis of pregnancy-related disorders and the potential therapeutic windows we can leverage to improve maternal and fetal outcomes.

Key points

  • Placental metabolism is shaped by a conflict between fetal demands and maternal constraints, with evidence from within the past 10 years confirming the existence of feto–placental genes that respond to metabolic–epigenetic interactions and fine-tune fetal development.

  • Placental trophoblast differentiation into the syncytiotrophoblast and extravillous trophoblasts ensures nutrient exchange, spiral artery remodelling and endocrine signalling critical for maternal adaptations and fetal development.

  • Metabolite sensing mechanisms and switches (such as O-GlcNAcylation, N-acylation, lactylation and methylation) have been discovered to dynamically regulate the epigenetic programming of particular lineages’ cell fates during feto–placental development.

  • Steroid-sensing nuclear hormone receptor signalling, oxygen-sensing hypoxia-inducible factor 1α (HIF1α) signalling and redox signalling also regulate tissue progenitor multipotency or lineage differentiation according to different levels of steroids and oxygen.

  • Metabolic–epigenetic disruptions (such as aberrant tricarboxylic acid levels, histone acetylation, DNA methylation or RNA methylation) impair feto–placental development, triggering recurrent miscarriage, pre-eclampsia or fetal growth restriction.

  • Feto–placental metabolic stress induces epigenetic reprogramming (such as 5-methylcytosine and N6-methyladenosine modifications), linking tissue progenitors to adult insulin resistance and developmental origins of adult-onset metabolic syndrome.

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Fig. 1: Fates of ESCs and TSCs during pregnancy.
Fig. 2: Nutrients, metabolites and epigenetic mechanisms that regulate cell fate in ESCs and TSCs.
Fig. 3: Metabolism and cell fates in pregnancy-related disease outcomes.

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Acknowledgements

The authors acknowledge the support of grants from the National Key Research and Development Program of China (grant no. 2022YFC2702400) and the National Natural Science Foundation of China (grant nos. 82421003, 82192872, 82495190, 32400655, U21A20396 and 2024YFA1802200).

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  1. These authors contributed equally: Yuanfeng Gao, Xin Yu, Yuefan Wang.

Authors and Affiliations

  1. State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

    Yuanfeng Gao, Xin Yu, Yuefan Wang, Hongmei Wang, Yan-Ling Wang & Ng Shyh-Chang

  2. Department of Cardiology, China–Japan Friendship Hospital, Beijing, China

    Yuanfeng Gao

  3. University of Chinese Academy of Sciences, Beijing, China

    Yuefan Wang, Hongmei Wang, Yan-Ling Wang & Ng Shyh-Chang

  4. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China

    Hongmei Wang, Yan-Ling Wang & Ng Shyh-Chang

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  5. Yan-Ling Wang
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All authors researched data for the article. N.S.-C., H.W. and Y.-L.W. contributed substantially to discussion of the content. N.S.-C., H.W., Y.-L.W., Y.G, X.Y. and Y.W. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Gao, Y., Yu, X., Wang, Y. et al. Metabolic control of feto–placental development and pregnancy outcomes. Nat Rev Endocrinol 22, 153–165 (2026). https://doi.org/10.1038/s41574-025-01206-9

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