Lysine-specific demethylase 3A (KDM3A) protects against ovarian dysfunction in premature ovarian insufficiency by transcriptional activation of ATP-binding cassette sub-family A member 7 (ABCA7)-mediated mitochondrial homeostasis.

Premature ovarian insufficiency (POI) is a heterogeneous disorder characterised by accelerated follicular depletion and ovarian dysfunction before age 40, yet effective therapeutic strategies remain limited. Here we identify the histone demethylase KDM3A (lysine‑specific demethylase 3A) as a critical protective factor in POI. We found that KDM3A expression is significantly downregulated in both granulosa cells from idiopathic POI patients and a cisplatin‑induced POI mouse model, and its levels correlate positively with serum AMH and oestradiol and negatively with FSH and LH. KDM3A‑deficient mice exhibited exacerbated cisplatin‑induced ovarian failure, with increased follicular atresia, elevated apoptosis, and hormonal imbalances, whereas ovarian‑specific KDM3A overexpression restored follicular development, oocyte quality, hormonal balance, and fertility. Mechanistically, chromatin immunoprecipitation sequencing identified ATP‑binding cassette sub‑family A member 7 (ABCA7) as a direct transcriptional target of KDM3A. KDM3A binds to the ABCA7 promoter, removes the repressive H3K9me2 mark, and activates ABCA7 transcription. KDM3A‑mediated ABCA7 upregulation preserves mitochondrial integrity, reduces oxidative stress, maintains mitochondrial membrane potential and ATP production, and suppresses granulosa cell apoptosis. Notably, ABCA7 overexpression alone phenocopied the protective effects of KDM3A, indicating that ABCA7 acts as a key downstream effector. Collectively, our findings uncover a previously unrecognised KDM3A‑ABCA7 epigenetic axis that safeguards mitochondrial homeostasis in granulosa cells. This pathway not only advances our understanding of POI pathogenesis but also provides potential molecular targets for therapeutic intervention in chemotherapy‑induced ovarian injury.