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

TL;DR

This study shows that HDAC3 in pregranulosa cells prevents cell death called ferroptosis, preserving the egg supply in females and ensuring fertility.

Contribution

The study reveals HDAC3's novel role in suppressing ferroptosis to maintain the primordial follicle reserve in pregranulosa cells.

Findings

HDAC3 deletion in pregranulosa cells leads to primordial follicle depletion and premature ovarian insufficiency.

Loss of HDAC3 triggers ferroptosis through dysregulation of genes controlling lipoxin biosynthesis and iron homeostasis.

Altered ferroptosis-related proteins confirm HDAC3's role in suppressing this cell death pathway.

Abstract

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.

The online version contains supplementary material available at 10.1007/s00018-026-06128-x.

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