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Objective <p>Recurrent pregnancy loss (RPL) affects approximately 1–5% of couples, yet its underlying causes remain poorly understood. Aberrant cellular senescence in the decidua has been implicated in pregnancy loss, but the molecular mechanisms controlling decidual senescence remain largely unknown. This study aimed to investigate the potential molecular mechanisms of RPL pathogenesis.</p> Methods <p>Decidual tissues were collected from RPL patients (<i>n</i> = 12) and healthy controls (<i>n</i> = 12), which underwent RNA sequencing. MAFF expression was assessed by immunohistochemistry and qPCR. Re-decidualized stromal cells (RDSCs) were transduced with MAFF-overexpressing lentivirus. Senescence was evaluated by SA-β-gal staining, EdU proliferation assays, and qPCR for senescence markers (CDKN2A, CDKN1A) and SASP factors (IL-6, IL-8, MMP3, MMP9, PAI-1). Mechanistic studies included immunofluorescence, co-immunoprecipitation, ChIP-qPCR, luciferase reporter assays, and ROS detection. The NRF2 agonist tBHQ was used for rescue experiments.</p> Results <p>RNA sequencing revealed that MAFF was significantly upregulated in the decidual tissue of RPL patients and positively correlated with senescence-related marker CDKN2A and MMP9 expression. MAFF overexpression in RDSCs induced cellular senescence, characterized by increased SA-β-gal activity, increased CDKN2A and CDKN1A expression, reduced proliferation, and induction of a robust SASP including IL-6, IL-8, MMP3, MMP9, and PAI-1. Mechanistically, MAFF physically interacted with NRF2, enhanced their nuclear co-localization, and competitively disrupted NRF2 binding to the ARE-F1 site within the NQO1 promoter, leading to reduced NQO1 expression and increased intracellular ROS levels. Notably, pharmacological activation of NRF2 with tBHQ reversed MAFF-induced senescence, restored proliferative capacity, downregulated CDKN2A and CDKN1A, and suppressed SASP factor expression.</p> Conclusions <p>Our findings identify MAFF as a critical negative regulator of NRF2-driven antioxidant defense in RDSCs. MAFF upregulation promotes oxidative stress and induces cellular senescence, thereby contributing to RPL pathogenesis. Targeting the MAFF-NRF2 axis with NRF2 agonists may represent a novel therapeutic strategy for RPL associated with decidual oxidative stress and senescence.</p>

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MAFF promotes decidual stromal cell senescence by suppressing NRF2-mediated antioxidant responses in recurrent pregnancy loss

  • 期刊论文

  • 发表日期：

    2026年7月28日

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  • Weihua He,
  • Yue Jin,
  • Lijun Yin,
  • Yating Zhao,
  • Yonghui Jiao,
  • Xitao Sun

摘要

Objective

Recurrent pregnancy loss (RPL) affects approximately 1–5% of couples, yet its underlying causes remain poorly understood. Aberrant cellular senescence in the decidua has been implicated in pregnancy loss, but the molecular mechanisms controlling decidual senescence remain largely unknown. This study aimed to investigate the potential molecular mechanisms of RPL pathogenesis.

Methods

Decidual tissues were collected from RPL patients (n = 12) and healthy controls (n = 12), which underwent RNA sequencing. MAFF expression was assessed by immunohistochemistry and qPCR. Re-decidualized stromal cells (RDSCs) were transduced with MAFF-overexpressing lentivirus. Senescence was evaluated by SA-β-gal staining, EdU proliferation assays, and qPCR for senescence markers (CDKN2A, CDKN1A) and SASP factors (IL-6, IL-8, MMP3, MMP9, PAI-1). Mechanistic studies included immunofluorescence, co-immunoprecipitation, ChIP-qPCR, luciferase reporter assays, and ROS detection. The NRF2 agonist tBHQ was used for rescue experiments.

Results

RNA sequencing revealed that MAFF was significantly upregulated in the decidual tissue of RPL patients and positively correlated with senescence-related marker CDKN2A and MMP9 expression. MAFF overexpression in RDSCs induced cellular senescence, characterized by increased SA-β-gal activity, increased CDKN2A and CDKN1A expression, reduced proliferation, and induction of a robust SASP including IL-6, IL-8, MMP3, MMP9, and PAI-1. Mechanistically, MAFF physically interacted with NRF2, enhanced their nuclear co-localization, and competitively disrupted NRF2 binding to the ARE-F1 site within the NQO1 promoter, leading to reduced NQO1 expression and increased intracellular ROS levels. Notably, pharmacological activation of NRF2 with tBHQ reversed MAFF-induced senescence, restored proliferative capacity, downregulated CDKN2A and CDKN1A, and suppressed SASP factor expression.

Conclusions

Our findings identify MAFF as a critical negative regulator of NRF2-driven antioxidant defense in RDSCs. MAFF upregulation promotes oxidative stress and induces cellular senescence, thereby contributing to RPL pathogenesis. Targeting the MAFF-NRF2 axis with NRF2 agonists may represent a novel therapeutic strategy for RPL associated with decidual oxidative stress and senescence.