Deficiency of placental GDF15 causes fetal growth restriction by inhibiting fetal hepatic STAT3-IGF2 axis
- 1Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China.
Abstract
Fetal growth restriction (FGR) is a major cause of perinatal morbidity and mortality, yet its underlying mechanism remains elusive. Here, we show that growth differentiation factor 15 (GDF15) levels are significantly reduced in the placenta and fetal circulation in mouse and pig FGR models and correlate positively with fetal weight. Placenta-specific GDF15 deficiency causes FGR, while placenta-specific Gdf15 mRNA delivery through targeted lipid nanoparticle (LNP) effectively alleviates FGR. Mechanistically, placental GDF15 is a major contributor to the fetal circulating GDF15 pool and enters the fetal compartment, where it activates the hepatic STAT3 signaling pathway to stimulate IGF2 production during pregnancy. Placental GDF15 deficiency decreases hepatic STAT3 phosphorylation and IGF2 levels in fetuses. Inhibition of STAT3 in primary mouse fetal hepatocytes blocks GDF15-induced IGF2 upregulation. Placenta-specific Gdf15 mRNA-LNP administration rescues the decreased hepatic p-STAT3 and IGF2 levels in FGR fetuses. Collectively, our findings identify a placenta-fetal liver metabolic axis where placental GDF15 promotes fetal growth by activating the fetal hepatic STAT3-IGF2 pathway, revealing a potential therapeutic target for FGR.
Circulating levels of GDF15 change during pregnancy, and low levels have been linked to fetal growth restriction in clinical studies. This study shows that placenta-specific GDF15 is required to support fetal growth in mice, and that it enters the fetal compartment to regulate hepatic metabolism.
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BibTeX
@article{liu2026deficiency,
title = {{Deficiency of placental GDF15 causes fetal growth restriction by inhibiting fetal hepatic STAT3-IGF2 axis}},
author = {Xiao Peng Liu and Xiao Zhang and Chun Xia Cai and Miao Miao Qin and Xiang Kai Leng and Jia Hao Chen and Yi Fan Han and Jun Ying Xiao and Jia He Huang and Jiang Wei Wu},
journal = {PLOS Biology},
year = {2026},
month = oct,
doi = {10.1371/journal.pbio.3004061},
url = {https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004061},
note = {CC BY},
}
RIS
TY - JOUR
TI - Deficiency of placental GDF15 causes fetal growth restriction by inhibiting fetal hepatic STAT3-IGF2 axis
AU - Xiao Peng Liu
AU - Xiao Zhang
AU - Chun Xia Cai
AU - Miao Miao Qin
AU - Xiang Kai Leng
AU - Jia Hao Chen
AU - Yi Fan Han
AU - Jun Ying Xiao
AU - Jia He Huang
AU - Jiang Wei Wu
PY - 2026
DA - 2026/10/14
JO - PLOS Biology
DO - 10.1371/journal.pbio.3004061
UR - https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004061
AB - Fetal growth restriction (FGR) is a major cause of perinatal morbidity and mortality, yet its underlying mechanism remains elusive. Here, we show that growth differentiation factor 15 (GDF15) levels are significantly reduced in the placenta and fetal circulation in mouse and pig FGR models and correlate positively with fetal weight. Placenta-specific GDF15 deficiency causes FGR, while placenta-specific Gdf15 mRNA delivery through targeted lipid nanoparticle (LNP) effectively alleviates FGR. Mechanistically, placental GDF15 is a major contributor to the fetal circulating GDF15 pool and enters the fetal compartment, where it activates the hepatic STAT3 signaling pathway to stimulate IGF2 production during pregnancy. Placental GDF15 deficiency decreases hepatic STAT3 phosphorylation and IGF2 levels in fetuses. Inhibition of STAT3 in primary mouse fetal hepatocytes blocks GDF15-induced IGF2 upregulation. Placenta-specific Gdf15 mRNA-LNP administration rescues the decreased hepatic p-STAT3 and IGF2 levels in FGR fetuses. Collectively, our findings identify a placenta-fetal liver metabolic axis where placental GDF15 promotes fetal growth by activating the fetal hepatic STAT3-IGF2 pathway, revealing a potential therapeutic target for FGR. Circulating levels of GDF15 change during pregnancy, and low levels have been linked to fetal growth restriction in clinical studies. This study shows that placenta-specific GDF15 is required to support fetal growth in mice, and that it enters the fetal compartment to regulate hepatic metabolism.
SN - 1545-7885
SN - 1544-9173
ER -