Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder among women of childbearing age and the leading cause of anovulatory infertility worldwide, with the death of granulosa cells implicated in its pathogenesis. However, the mechanisms underlying granulosa cell death remain unclear. Limited research has explored the association between GATA binding factor 1 (GATA1) and adverse pregnancy outcomes, yet its role in PCOS is still elusive. This study established an in vivo PCOS model via dehydroepiandrosterone administration in mice and used ovarian-like KGN cells to explore granulosa cell function. Results showed elevated ovarian GATA1 expression in PCOS mice. Functionally, GATA1 overexpression in KGN cells increased lipid reactive oxygen species, malondialdehyde, and iron, while reducing glutathione. Notably, all these effects of GATA1 were mitigated by a ferroptosis inhibitor Ferrostatin-1. Furthermore, GATA1 knockdown alleviated lipid peroxidation and iron overload in KGN cells induced by a ferroptosis inducer Erastin. Mechanistically, GATA1 directly bound the transferrin receptor (TFRC) promoter to enhance its transcription. Additionally, TFRC overexpression counteracted GATA1 knockdown’s protective effects against Erastin-induced ferroptosis. Collectively, GATA1 promotes granulosa cell ferroptosis via TFRC transcriptional activation, contributing to PCOS pathogenesis. GATA1 regulatory pathways may serve as potential therapeutic targets for PCOS.
Wang et al. (2026) studied this question.