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<p>Early-onset preeclampsia (EOPE) with fetal growth restriction (FGR) is a severe hypertensive disorder of pregnancy characterized by placental dysfunction and estrogen deficiency. Based on single-cell RNA sequencing (scRNA-seq) profiling of specific placental trophoblast subtypes from EOPE-FGR and normotensive pregnancies, we identified <i>HSD17B1</i>, which encodes a key enzyme mediating estradiol conversion, as the central dysregulated node in EOPE pathogenesis. Multi-modal computational analysis (cluster annotation, cellular proportion calculation, comparison of differentially expressed genes, and characterization of cellular developmental trajectories) revealed key expression dynamics during syncytiotrophoblast (SCT) differentiation, with substantial suppression in EOPE specimens. Further validation using clinical placental samples confirmed the downregulation of HSD17B1 at the protein level in patients with EOPE, as demonstrated by immunohistochemistry and western blotting. Mechanistically, <i>HSD17B1</i> knockdown in BeWo trophoblast models recapitulated the core EOPE phenotypes of impaired SCT differentiation and estrogen biosynthesis blockade. These findings reveal that HSD17B1 is a master coordinator of trophoblast-endocrine crosstalk, the impairment of which in placental trophoblasts may contribute to EOPE pathogenesis. Our findings provide a mechanistic basis for developing HSD17B1-targeted interventions that could contribute to the concurrent restoration of placental competence and hormonal regulation, improving the perinatal outcomes of patients with EOPE.</p>

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HSD17B1-mediated trophoblast differentiation lowers estrogen levels in early-onset preeclampsia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月20日

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  • Shu Zheng,
  • Wei Feng,
  • Zewen Sun,
  • Peng Xu,
  • Shuai Dong,
  • Lin Pan,
  • Huimin Shen,
  • Jin He,
  • Peng Chen,
  • Chang Shu

摘要

Early-onset preeclampsia (EOPE) with fetal growth restriction (FGR) is a severe hypertensive disorder of pregnancy characterized by placental dysfunction and estrogen deficiency. Based on single-cell RNA sequencing (scRNA-seq) profiling of specific placental trophoblast subtypes from EOPE-FGR and normotensive pregnancies, we identified HSD17B1, which encodes a key enzyme mediating estradiol conversion, as the central dysregulated node in EOPE pathogenesis. Multi-modal computational analysis (cluster annotation, cellular proportion calculation, comparison of differentially expressed genes, and characterization of cellular developmental trajectories) revealed key expression dynamics during syncytiotrophoblast (SCT) differentiation, with substantial suppression in EOPE specimens. Further validation using clinical placental samples confirmed the downregulation of HSD17B1 at the protein level in patients with EOPE, as demonstrated by immunohistochemistry and western blotting. Mechanistically, HSD17B1 knockdown in BeWo trophoblast models recapitulated the core EOPE phenotypes of impaired SCT differentiation and estrogen biosynthesis blockade. These findings reveal that HSD17B1 is a master coordinator of trophoblast-endocrine crosstalk, the impairment of which in placental trophoblasts may contribute to EOPE pathogenesis. Our findings provide a mechanistic basis for developing HSD17B1-targeted interventions that could contribute to the concurrent restoration of placental competence and hormonal regulation, improving the perinatal outcomes of patients with EOPE.