Abstract
Abnormal senescence of decidual stromal cells (DSCs) is tightly linked to spontaneous abortion, yet the underlying mechanisms remain poorly defined. In this study, we found that DSC senescence was significantly increased in the decidual tissues of patients with recurrent spontaneous abortion (RSA) during the first trimester. Using both in vitro and in vivo models, we show that abnormally elevated branched-chain amino acids (BCAAs) reduce autophagic flux, leading to excessive DSC senescence, which mechanistically involves aberrant heat shock protein A6 (HSPA6) upregulation and subsequent downregulation of the transcription factor forkhead box O1 (FOXO1), thereby predisposing to adverse pregnancy outcomes. In vivo studies, intervention with leucine, a key BCAA, promoted uterine senescence and induced adverse pregnancy outcomes in mice. Conversely, restoring autophagy with rapamycin effectively suppressed excessive senescence at the maternal-fetal interface and significantly improved pregnancy outcomes under high-leucine conditions. Therefore, this study demonstrates that excessive senescence at the maternal-fetal interface resulting from impaired autophagic flux disrupts pregnancy maintenance via the HSPA6-FOXO1 signaling pathway. These findings highlight the roles of metabolic dysregulation and autophagy imbalance in miscarriage and provide a potential mechanistic basis for therapeutic strategies to prevent spontaneous abortion.
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Abbreviations
- ATG4A:
-
autophagy-related 4 A cysteine peptidase
- ATG4B:
-
autophagy-related 4B cysteine peptidase
- ATG5:
-
autophagy-related 5
- BafA1:
-
Bafilomycin A1
- BCAA:
-
branched-chain amino acid
- BECN1:
-
beclin 1
- CDKN2A/p16:
-
cyclin-dependent kinase inhibitor 2 A
- CDKN1A/p21:
-
cyclin-dependent kinase inhibitor 1 A
- DEGs:
-
differentially expressed genes
- D-Gal:
-
D-galactose
- DSC:
-
decidual stromal cell
- FOXO1:
-
forkhead box O1
- GAPDH:
-
glyceraldehyde-3-phosphate dehydrogenase
- HSPA6:
-
heat shock protein family A member 6
- Leu:
-
leucine
- MAP1LC3A/LC3A:
-
microtubule associated protein 1 light chain 3 alpha
- MAP1LC3B/LC3B:
-
microtubule-associated protein 1 light chain 3 beta
- mTOR:
-
mechanistic target of rapamycin kinase
- mTORC1:
-
mechanistic target of rapamycin complex 1
- NP:
-
normal pregnancy
- Rapa:
-
rapamycin
- ROS:
-
reactive oxygen species
- RSA:
-
recurrent spontaneous abortion
- SA-β-gal:
-
senescence-associated β-galactosidase
- SASP:
-
senescence-associated secretory phenotype
- siHSPA6 DSCs:
-
HSPA6-silenced DSCs
- SQSTM1/p62:
-
sequestosome 1
- TP53/p53:
-
tumor protein p53
- 3-MA:
-
3-methyladenine
Acknowledgements
We are grateful to the staff at Shanghai Genechem Co., Ltd. for their assistance with bioinformatics analysis.
Funding
This study was supported by the National Key Research and Development Program of China (2023YFC2705403), the National Natural Science Foundation of China (NSFC 82371673, 82301857, 32370914, 92478122, 92357306), the Shanghai Oriental Talent Plan, and the Shanghai Natural Science Foundation (17ZR1403200).
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The study protocol was approved by the Human Ethics Committee of the Obstetrics and Gynecology Hospital of Fudan University (approval No. 2023 − 136), and all participants provided written informed consent in accordance with the Declaration of Helsinki. All animal experiments were approved by the Animal Ethics Committee of Fudan University (approval No. 202311012 S) and performed in accordance with the Guide for the Care and Use of Laboratory Animals.
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Tan, HX., Yang, SL., Shi, JW. et al. Aberrant autophagy–senescence axis drives spontaneous abortion through HSPA6/FOXO1-mediated decidual stromal dysfunction. Cell. Mol. Life Sci. (2026). https://doi.org/10.1007/s00018-026-06508-3
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DOI: https://doi.org/10.1007/s00018-026-06508-3