2. Academic Validation
  3. Endometrial stromal cell-derived TMAO sustains decidualization to prevent recurrent spontaneous abortion

Endometrial stromal cell-derived TMAO sustains decidualization to prevent recurrent spontaneous abortion

  • Cell Metab. 2026 Feb 3;38(2):316-330.e8. doi: 10.1016/j.cmet.2025.11.014.
Yu-Ling Chen 1,  Lin-Chen Tang 2,  Wei Zhou 1,  Xin Sun 1,  Zhen-Zhen Lai 3,  Sha Xu 1,  Ke Cai 1,  Yan Shi 1,  Rui Zhao 1,  Xiang-Yu Zhou 3,  Jun Jim Zhang 1,  Fei Li 1,  Bo Li 4,  Ming-Qing Li 5,  Li-Ping Jin 6,  Jian-Yuan Zhao 7
Affiliations

Affiliations

  • 1 Ministry of Education, Shanghai Key Laboratory of Children's Environmental Health, Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai, China; Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center, Department of Biobank, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 3 Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai, China.
  • 4 Ministry of Education, Shanghai Key Laboratory of Children's Environmental Health, Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
  • 5 Department of Reproductive Immunology, The International Peace Maternity and Child Health Hospital of China Welfare Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
  • 6 Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai, China; Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center, Department of Biobank, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China. Electronic address: [email protected].
  • 7 Ministry of Education, Shanghai Key Laboratory of Children's Environmental Health, Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
PMID: 41512878 DOI: 10.1016/j.cmet.2025.11.014
Abstract

Recurrent spontaneous abortion (RSA), often linked to defective endometrial stromal cell (ESC) decidualization, lacks effective metabolism-targeted therapies. Here, we identify the in situ synthesis of trimethylamine N-oxide (TMAO) in human decidua as a critical safeguard. Metabolomics revealed significantly lower TMAO levels in decidual tissues of individuals experiencing RSA. Mechanistically, cyclic AMP (cAMP)-protein kinase A (PKA)-cAMP-responsive element-binding protein 1 (CREB1) signaling upregulated flavin-containing monooxygenase 3 (FMO3) in ESCs, driving local TMAO accumulation. TMAO directly bound the C terminus of 14-3-3η, enhancing its interaction with phosphoinositide-dependent protein kinase 1 (PDK1) to relieve PDK1-mediated suppression of forkhead box protein O1 (FOXO1). This promoted FOXO1 nuclear translocation and the activation of decidualization markers. Through mouse models employing dietary choline restriction, and FMO3 inhibition via pharmacological or genetic knockout, we demonstrated that endometrial TMAO deficiency impairs decidualization and increases pregnancy loss. Strikingly, TMAO restored decidualization capacity in 15% of patient-derived ESCs with inherent dysfunction. Our findings unveil endometrial TMAO synthesis as a metabolic checkpoint for decidualization and propose it as a therapeutic candidate for RSA.

Keywords

14-3-3η; endometrial stromal cell; forkhead box protein O1; recurrent spontaneous abortion; trimethylamine N-oxide.

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