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<p>Intrahepatic cholestasis of pregnancy (ICP) is characterized by bile acid accumulation, placental dysfunction, and adverse perinatal outcomes. However, there is currently no reliable tool to predict the occurrence of severe ICP or its associated complications, and its pathophysiology remains incompletely understood. The objective of this study was to identify more sensitive and specific biomarkers for the clinical diagnosis, early prediction, and prognostic assessment of adverse outcomes in ICP, and to explore the biological relevance of the identified pathway at the maternal–fetal interface. We performed integrated serum metabolomic–proteomic analysis, followed by trimester-specific clinical validation, placental tissue analysis, in vitro trophoblast experiments, and in vivo validation in an estrogen-induced ICP rat model. Exploratory multi-omics analysis highlighted the thyroxine-binding globulin–thyroxine (TBG–T4) axis, related to thyroid hormone transport and availability, as a biologically relevant pathway in ICP. Although total and free T4 remained within physiological reference ranges, circulating TBG, total T4, and free T4 were significantly reduced across pregnancy in women with ICP and were associated with biochemical cholestasis, earlier delivery, and lower neonatal birth weight. Mechanistic analyses showed that reduced TBG availability was associated with decreased local T4 availability and enhanced trophoblast apoptosis under bile acid stress. In the ICP rat model, Ad-TBG-mediated TBG overexpression partially restored thyroid hormone homeostasis, attenuated placental and hepatic injury, and improved fetal growth and survival. These findings identify disruption of the TBG–T4 axis as a mechanistic link between cholestatic stress, impaired thyroid hormone availability, and trophoblast apoptosis in ICP.</p>

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Bile acid-induced TBG depletion promotes trophoblast apoptosis via local thyroxine insufficiency in intrahepatic cholestasis of pregnancy

  • 期刊论文

  • 发表日期：

    2026年6月29日

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  • Gaoying Wang,
  • Wen Hu,
  • Jianyi Gao,
  • Rong Wang,
  • Ting Zhang,
  • Ruirui Dong

摘要

Intrahepatic cholestasis of pregnancy (ICP) is characterized by bile acid accumulation, placental dysfunction, and adverse perinatal outcomes. However, there is currently no reliable tool to predict the occurrence of severe ICP or its associated complications, and its pathophysiology remains incompletely understood. The objective of this study was to identify more sensitive and specific biomarkers for the clinical diagnosis, early prediction, and prognostic assessment of adverse outcomes in ICP, and to explore the biological relevance of the identified pathway at the maternal–fetal interface. We performed integrated serum metabolomic–proteomic analysis, followed by trimester-specific clinical validation, placental tissue analysis, in vitro trophoblast experiments, and in vivo validation in an estrogen-induced ICP rat model. Exploratory multi-omics analysis highlighted the thyroxine-binding globulin–thyroxine (TBG–T4) axis, related to thyroid hormone transport and availability, as a biologically relevant pathway in ICP. Although total and free T4 remained within physiological reference ranges, circulating TBG, total T4, and free T4 were significantly reduced across pregnancy in women with ICP and were associated with biochemical cholestasis, earlier delivery, and lower neonatal birth weight. Mechanistic analyses showed that reduced TBG availability was associated with decreased local T4 availability and enhanced trophoblast apoptosis under bile acid stress. In the ICP rat model, Ad-TBG-mediated TBG overexpression partially restored thyroid hormone homeostasis, attenuated placental and hepatic injury, and improved fetal growth and survival. These findings identify disruption of the TBG–T4 axis as a mechanistic link between cholestatic stress, impaired thyroid hormone availability, and trophoblast apoptosis in ICP.