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<p>The non-renewable primordial follicle (PF) pool underlies female reproductive longevity, yet PF numbers decline sharply before puberty for reasons that remain unclear. Here, we identify histone deacetylase 3 (HDAC3) in pregranulosa cells (pGCs) as a key suppressor of ferroptosis in PFs. Constitutively low HDAC3 expression in pGCs is essential for PF survival: conditional deletion of <i>Hdac3</i> caused profound PF depletion and ultimately premature ovarian insufficiency. Loss of HDAC3 preferentially triggered ferroptosis, as supported by ferroptosis-associated transcriptional signatures and dysregulation of genes governing lipoxin biosynthesis and cellular iron homeostasis following <i>Hdac3</i> depletion. Correspondingly, alterations in proteins central to ferroptotic pathways corroborated this mechanism. Together, these findings demonstrate that constitutive HDAC3 expression in pGCs safeguards the PF reserve by restraining ferroptosis and is therefore indispensable for female fertility.</p>

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HDAC3 Preserves the primordial follicle reserve by epigenetically suppressing ferroptosis in pregranulosa cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月9日

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  • Ziqi Chen,
  • Jiantao Guo,
  • Meng Gao,
  • Huarong Wang,
  • Han Cai,
  • Qingfeng Yang,
  • Xinyu Yang,
  • Yi Lin,
  • Zijian Zhu,
  • Shaogang Qin,
  • Yibing Bao,
  • Ting Zhao,
  • Longping Liu,
  • Tengteng Wang,
  • Bo Zhou,
  • Hua Zhang,
  • Jianbin Wang,
  • Hua Guo,
  • Guoliang Xia,
  • Chao Wang

摘要

The non-renewable primordial follicle (PF) pool underlies female reproductive longevity, yet PF numbers decline sharply before puberty for reasons that remain unclear. Here, we identify histone deacetylase 3 (HDAC3) in pregranulosa cells (pGCs) as a key suppressor of ferroptosis in PFs. Constitutively low HDAC3 expression in pGCs is essential for PF survival: conditional deletion of Hdac3 caused profound PF depletion and ultimately premature ovarian insufficiency. Loss of HDAC3 preferentially triggered ferroptosis, as supported by ferroptosis-associated transcriptional signatures and dysregulation of genes governing lipoxin biosynthesis and cellular iron homeostasis following Hdac3 depletion. Correspondingly, alterations in proteins central to ferroptotic pathways corroborated this mechanism. Together, these findings demonstrate that constitutive HDAC3 expression in pGCs safeguards the PF reserve by restraining ferroptosis and is therefore indispensable for female fertility.