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