{
  "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.\n\nCirculating 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.",
  "abstract_shown": true,
  "affiliations": [
    "Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China."
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Xiao Peng Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiao Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Chun Xia Cai"
    },
    {
      "affs": [
        0
      ],
      "name": "Miao Miao Qin"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiang Kai Leng"
    },
    {
      "affs": [
        0
      ],
      "name": "Jia Hao Chen"
    },
    {
      "affs": [
        0
      ],
      "name": "Yi Fan Han"
    },
    {
      "affs": [
        0
      ],
      "name": "Jun Ying Xiao"
    },
    {
      "affs": [
        0
      ],
      "name": "Jia He Huang"
    },
    {
      "affs": [
        0
      ],
      "name": "Jiang Wei Wu",
      "orcid": "0000-0002-6183-6368"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9106v8g8t0j9w.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.pbio.3004061",
  "fulltext_url": "https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004061",
  "id": "9106v8g8t0j9w",
  "issns": [
    "1545-7885",
    "1544-9173"
  ],
  "landing_url": "https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004061",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2729|Pregnancy and preeclampsia studies"
    ],
    [
      "plos",
      "/Biology and life sciences/Anatomy/Liver/Hepatocytes"
    ],
    [
      "plos",
      "/Biology and life sciences/Anatomy/Reproductive system/Placenta"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Hepatocytes"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Signal transduction/Cell signaling/Endocrine signaling"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Signal transduction/Cell signaling/STAT signaling"
    ],
    [
      "plos",
      "/Biology and life sciences/Developmental biology/Embryology/Fetuses"
    ],
    [
      "plos",
      "/Biology and life sciences/Developmental biology/Embryology/Placenta"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Endocrine physiology/Endocrine signaling"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Physiological parameters/Body weight"
    ],
    [
      "plos",
      "/Medicine and health sciences/Anatomy/Liver/Hepatocytes"
    ],
    [
      "plos",
      "/Medicine and health sciences/Anatomy/Reproductive system/Placenta"
    ],
    [
      "plos",
      "/Medicine and health sciences/Endocrinology/Endocrine physiology/Endocrine signaling"
    ],
    [
      "plos",
      "/Medicine and health sciences/Women's health/Maternal health/Pregnancy"
    ],
    [
      "plos",
      "/Medicine and health sciences/Women's health/Obstetrics and gynecology/Pregnancy"
    ],
    [
      "plos",
      "/Research and analysis methods/Animal studies/Experimental organism systems/Animal models/Mouse models"
    ],
    [
      "plos",
      "/Research and analysis methods/Animal studies/Experimental organism systems/Model organisms/Mouse models"
    ],
    [
      "plos",
      "/Research and analysis methods/Model organisms/Mouse models"
    ]
  ],
  "openalex": "W7221830317",
  "pdf_url": "https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3004061&type=printable",
  "pmcid": "PMC13686457",
  "pmid": "42873832",
  "published": "2026-10-14",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/9106v8g8t0j9w.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:23Z",
      "native_id": "10.1371/journal.pbio.3004061",
      "source": "plos",
      "url": "https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004061"
    },
    {
      "first_seen": "2026-10-30T12:18:46Z",
      "native_id": "MED:42873832",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42873832"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "plos:cell biology",
      "subfield": "cell-biology"
    },
    {
      "field": "medicine",
      "origin": "plos:anatomy",
      "subfield": "physiology"
    }
  ],
  "title": "Deficiency of placental GDF15 causes fetal growth restriction by inhibiting fetal hepatic STAT3-IGF2 axis",
  "title_text": "Deficiency of placental GDF15 causes fetal growth restriction by inhibiting fetal hepatic STAT3-IGF2 axis",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:18:46Z",
  "url": "https://research.draconitic.com/paper/9106v8g8t0j9w",
  "venue": "PLOS Biology",
  "versions": []
}