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Background <p>Optimal endometrial thickness and receptivity, precisely regulated by steroid hormones, are critical determinants for successful embryo implantation. Thin endometrium is a major cause of female infertility, yet its pathogenesis requires further exploration. Cellular proliferation and differentiation are highly dependent on the activation status of intracellular metabolic signaling pathways, among which the mammalian target of rapamycin (mTOR) signaling pathway serves as a central metabolic integrator. However, the mechanistic links between mTOR dysregulation, metabolic reprogramming, and endometrial regenerative failure remain poorly understood, representing a critical knowledge gap in reproductive medicine.</p> Methods <p>Uterine-specific Raptor knockout mice (<i>Rptor</i><sup><i>fl/fl</i></sup><i>Pgr</i><sup><i>cre/</i>+</sup>) were generated using the Cre-LoxP system. Endometrial pathology was assessed through multi-dimensional analyses: (1) hematoxylin–eosin staining, immunofluorescence, and T2-weighted magnetic resonance imaging were used to quantify endometrial dimensions, glandular development, and vascularization; (2) Functional competence was evaluated via the Pollard experiment and artificial decidualization models to assess receptivity and decidualization; (3) Molecular mechanisms were dissected using high-throughput RNA sequencing and flow cytometry to profile mTORC1-mediated cholesterol synthesis signaling, endometrial renewal, and cell cycle progression.</p> Results <p><i>Rptor</i><sup><i>fl/fl</i></sup><i>Pgr</i><sup><i>cre/</i>+</sup> mice recapitulated key features of thin endometrium syndrome, exhibiting significantly reduced endometrial thickness, impaired glandular development, and defective vascularization. Despite having comparable estrogen and progesterone levels, these mice displayed profound endometrial receptivity defects and impaired decidual response. Raptor deficiency attenuated cell proliferation by disrupting lipid metabolism pathways, consequently impairing estrogen responsiveness and diminishing uterine regenerative capacity.</p> Conclusions <p>Our study establishes that mTORC1 signaling orchestrates hormone-responsive endometrial proliferation through metabolic regulation, fundamentally underpinning endometrial receptivity and decidualization. These findings provide mechanistic insights into the pathogenesis of thin endometrium and highlight potential therapeutic targets for infertility treatment.</p> Graphical Abstract <p></p>

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mTORC1 as a metabolic rheostat coordinates hormonal signals and cellular proliferation to sustain endometrial competence

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月13日

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  • Yadong Sun,
  • Shuo Wan,
  • Mingyue Zhao,
  • Kexin Chen,
  • Yue Wu,
  • Yong Huang,
  • Jun He,
  • Feng Liu,
  • Hanlin Shuai,
  • Jiacong Yan,
  • Meixiang Yang

摘要

Background

Optimal endometrial thickness and receptivity, precisely regulated by steroid hormones, are critical determinants for successful embryo implantation. Thin endometrium is a major cause of female infertility, yet its pathogenesis requires further exploration. Cellular proliferation and differentiation are highly dependent on the activation status of intracellular metabolic signaling pathways, among which the mammalian target of rapamycin (mTOR) signaling pathway serves as a central metabolic integrator. However, the mechanistic links between mTOR dysregulation, metabolic reprogramming, and endometrial regenerative failure remain poorly understood, representing a critical knowledge gap in reproductive medicine.

Methods

Uterine-specific Raptor knockout mice (Rptorfl/flPgrcre/+) were generated using the Cre-LoxP system. Endometrial pathology was assessed through multi-dimensional analyses: (1) hematoxylin–eosin staining, immunofluorescence, and T2-weighted magnetic resonance imaging were used to quantify endometrial dimensions, glandular development, and vascularization; (2) Functional competence was evaluated via the Pollard experiment and artificial decidualization models to assess receptivity and decidualization; (3) Molecular mechanisms were dissected using high-throughput RNA sequencing and flow cytometry to profile mTORC1-mediated cholesterol synthesis signaling, endometrial renewal, and cell cycle progression.

Results

Rptorfl/flPgrcre/+ mice recapitulated key features of thin endometrium syndrome, exhibiting significantly reduced endometrial thickness, impaired glandular development, and defective vascularization. Despite having comparable estrogen and progesterone levels, these mice displayed profound endometrial receptivity defects and impaired decidual response. Raptor deficiency attenuated cell proliferation by disrupting lipid metabolism pathways, consequently impairing estrogen responsiveness and diminishing uterine regenerative capacity.

Conclusions

Our study establishes that mTORC1 signaling orchestrates hormone-responsive endometrial proliferation through metabolic regulation, fundamentally underpinning endometrial receptivity and decidualization. These findings provide mechanistic insights into the pathogenesis of thin endometrium and highlight potential therapeutic targets for infertility treatment.

Graphical Abstract