BEIJING, CHINA – Primordial follicles form the lifelong ovarian reserve in females. Most enter dormancy after birth and remain inactive for decades, while a small fraction develops immediately. The mechanism sustaining this dormancy has long been unclear.
In a breakthrough study published in Science Bulletin , researchers from China Agricultural University (CAU) and the Beijing Institute of Life Sciences revealed that histone demethylase LSD1 acts as an essential epigenetic regulator for maintaining dormant primordial follicles.
Using fetal-stage oocyte-specific Lsd1 knockout mice, the team discovered that LSD1 deficiency caused rapid depletion of the primordial follicle pool. Strikingly, only dormant follicles ("second wave") were affected – actively developing follicles ("first wave") remained intact and could ovulate normally.
Mechanistically, LSD1 loss elevated H3K4me3 levels at promoters of Foxo3 and mitophagy-related genes, suppressing their expression. This disrupted mitochondrial recycling, accumulated reactive oxygen species (ROS), and triggered ferroptosis – an iron-dependent cell death pathway. Single-cell transcriptomics and histone profiling confirmed these changes exclusively in dormant follicle oocytes.
"LSD1 serves as a molecular switch distinguishing dormant and active follicles," said corresponding author Prof. Chao Wang. "Its absence collapses redox balance, turning dormant follicles into ferroptosis victims while sparing active ones."
This work builds on the team’s earlier finding that low ROS levels sustain dormancy. It now establishes LSD1-controlled mitophagy as the core mechanism preventing ferroptosis and preserving ovarian reserve.
Funding :
The National Key Research & Developmental Program of China, the National Natural Science Foundation of China, the Innovative Project of the State Key Laboratory of Animal Biotech Breeding, and the 2115 Talent Development Program of China Agricultural University.
Science Bulletin
Experimental study