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<p>Reproductive longevity is essential for female fertility and healthy aging; however, the role of stress response, especially stress granule accumulation, in ovarian aging remains elusive and interventions are lacking. Here, we identified deleterious mutations and decreased expression of NCOA7, a stress-response protein related to granulosa cell senescence in women with physiological and pathological ovarian aging. NCOA7 deletion accelerates oxidative stress-related cellular senescence, ovarian aging and fecundity decline in mice. Mechanistically, NCOA7 partitions into the stress granule containing G3BP1–V-ATPase and facilitates autophagic degradation of stress granules to relieve stress. Boosting granulophagy with rapamycin or lipid nanoparticle-based mRNA delivery of <i>NCOA7</i> accelerates stress granule clearance, alleviating cellular senescence in human granulosa cells and delaying ovarian aging in mice. This study depicts a mechanism for ovarian resilience to stress and provides potential targets for therapeutic strategies to alleviate ovarian aging.</p>

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Stress granule clearance mediated by V-ATPase-interacting protein NCOA7 mitigates ovarian aging

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月31日

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  • Ting Dong,
  • Nianyu Li,
  • Huirui Wang,
  • Hanbing Zhu,
  • Yinghui Gao,
  • Yue Liu,
  • Fang Fang,
  • Xiaojie Fu,
  • Pinxin Si,
  • Cheng Li,
  • Mei Li,
  • Fei Wang,
  • Shidou Zhao,
  • Ting Guo,
  • Linlin Cui,
  • Xinyi Jiang,
  • Xiaohui Liu,
  • Han Zhao,
  • Yingying Qin,
  • Zi-Jiang Chen,
  • Hongxiang Lou,
  • Xue Jiao

摘要

Reproductive longevity is essential for female fertility and healthy aging; however, the role of stress response, especially stress granule accumulation, in ovarian aging remains elusive and interventions are lacking. Here, we identified deleterious mutations and decreased expression of NCOA7, a stress-response protein related to granulosa cell senescence in women with physiological and pathological ovarian aging. NCOA7 deletion accelerates oxidative stress-related cellular senescence, ovarian aging and fecundity decline in mice. Mechanistically, NCOA7 partitions into the stress granule containing G3BP1–V-ATPase and facilitates autophagic degradation of stress granules to relieve stress. Boosting granulophagy with rapamycin or lipid nanoparticle-based mRNA delivery of NCOA7 accelerates stress granule clearance, alleviating cellular senescence in human granulosa cells and delaying ovarian aging in mice. This study depicts a mechanism for ovarian resilience to stress and provides potential targets for therapeutic strategies to alleviate ovarian aging.