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<p>Increasing evidence suggests that non-coding small RNAs (miRNAs) carried by exosomes (EXOs) play important roles in the development and treatment of polycystic ovary syndrome (PCOS). In this study, we demonstrate that PCOS mouse serum-derived EXOs promote granulosa cells (GCs) ferroptosis, and induce the occurrence of a PCOS-like phenotype in vivo. Notably, EXO miRNA sequencing combined with in vitro gain- and loss-of-function assays revealed that miR-128-3p, which is absent in the serum-derived EXOs of mice with PCOS, regulates lipid peroxidation and GC sensitivity to ferroptosis inducers. Mechanistically, overexpression of <i>CSF1</i>, a direct target of miR-128-3p, reversed the anti-ferroptotic effect of miR-128-3p. Conversely, ferroptosis induction was mitigated in <i>CSF1</i>-downregulated GCs. Furthermore, we demonstrated that miR-128-3p inhibition activates the p38/JNK pathway via <i>CSF1</i>, leading to NRF2-mediated down-regulation of <i>SLC7A11</i> transcription, which triggers GC iron overload. Moreover, intrathecal miR-128-3p AgomiR injection into mouse ovaries ameliorated PCOS-like characteristics and restored fertility in letrozole-induced mice. The study reveals the pathological mechanisms of PCOS based on circulating EXOs and provides the first evidence of the roles of miR-128-3p and <i>CSF1</i> in ovarian GCs. This discovery is expected to provide promising therapeutic targets for the treatment of PCOS.</p><p></p>

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Decreased miR-128-3p in serum exosomes from polycystic ovary syndrome induces ferroptosis in granulosa cells via the p38/JNK/SLC7A11 axis through targeting CSF1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月18日

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  • Yanqiu Lv,
  • Shengzhong Han,
  • Fuliang Sun,
  • Yuyang Zhang,
  • Xinglin Qu,
  • Hao Li,
  • Weiyu Gu,
  • Qinglong Xu,
  • Shunfa Yao,
  • Xuan Chen,
  • Yi Jin

摘要

Increasing evidence suggests that non-coding small RNAs (miRNAs) carried by exosomes (EXOs) play important roles in the development and treatment of polycystic ovary syndrome (PCOS). In this study, we demonstrate that PCOS mouse serum-derived EXOs promote granulosa cells (GCs) ferroptosis, and induce the occurrence of a PCOS-like phenotype in vivo. Notably, EXO miRNA sequencing combined with in vitro gain- and loss-of-function assays revealed that miR-128-3p, which is absent in the serum-derived EXOs of mice with PCOS, regulates lipid peroxidation and GC sensitivity to ferroptosis inducers. Mechanistically, overexpression of CSF1, a direct target of miR-128-3p, reversed the anti-ferroptotic effect of miR-128-3p. Conversely, ferroptosis induction was mitigated in CSF1-downregulated GCs. Furthermore, we demonstrated that miR-128-3p inhibition activates the p38/JNK pathway via CSF1, leading to NRF2-mediated down-regulation of SLC7A11 transcription, which triggers GC iron overload. Moreover, intrathecal miR-128-3p AgomiR injection into mouse ovaries ameliorated PCOS-like characteristics and restored fertility in letrozole-induced mice. The study reveals the pathological mechanisms of PCOS based on circulating EXOs and provides the first evidence of the roles of miR-128-3p and CSF1 in ovarian GCs. This discovery is expected to provide promising therapeutic targets for the treatment of PCOS.