Genistein mitigates ovarian dysfunction in a PCOS mouse model by regulating steroidogenesis, apoptosis, and PARP-1 signaling

Jin Wang; Fenglan Lu; Zhuoqian Guo; Qiuxian Meng; Tingting Gou; Wenkai Li; Xiaojuan Wan; Muhammad Faheem Akhtar; Mahmoud M. Azzam; Guoyun Wu

Just Accepted

This article has been peer reviewed and accepted for publication. It is in production and has not been edited, so may differ from the final published form.

Genistein mitigates ovarian dysfunction in a PCOS mouse model by regulating steroidogenesis, apoptosis, and PARP-1 signaling

Jin Wang, Fenglan Lu, Zhuoqian Guo, Qiuxian Meng, Tingting Gou, Wenkai Li, Xiaojuan Wan, Muhammad Faheem Akhtar, Mahmoud M. Azzam, Guoyun Wu

Abstract

Context. Polycystic ovary syndrome (PCOS) is a common endocrine disorder marked by hormonal and clinical imbalances. Genistein (GEN), a soy isoflavone with antioxidant properties, has shown promise in PCOS treatment, though its mechanisms remain unclear. Aims. This study aimed to investigate the effects of genistein on ovarian dysfunction in a letrozole-induced PCOS mouse model, focusing on steroidogenesis, apoptosis, and PARP-1 signaling. Methods. PCOS was induced by oral administration of letrozole (37.5 mg/kg/day) for 21 days. Mice were then divided into three groups (n = 10 each) for another 21-day treatment: control (corn oil), PCOS (continued letrozole), and PCOS+GEN (letrozole + genistein, 50 mg/kg/day, i.p.). Key results. Genistein restored estrous cyclicity in 80% of treated mice versus 0% in the PCOS group (p < 0.05). Histologically, it improved follicular morphology, increased granulosa cell thickness and density, and promoted corpora lutea formation. Genistein significantly reduced serum T and P4 levels (p < 0.05) and modulated expression of steroidogenic proteins (CYP11A1, CYP19A1, STAR). It also decreased cleaved Caspase-3 and cleaved PARP-1 expression (p < 0.05), and suppressed abnormal PARylation without affecting total PARP-1 levels. Conclusions. Genistein alleviates ovarian dysfunction in PCOS mice by restoring estrous cyclicity, enhancing follicular development, and normalizing hormone levels, through regulation of steroidogenic proteins, inhibition of apoptosis, and modulation of PARP-1 activity. Implications. These findings support genistein as a potential therapeutic agent for PCOS, targeting the PARP-1/pADPr axis and apoptosis. Further studies are needed to explore upstream mechanisms and evaluate its long-term effects on reproductive health.

RD25126 Accepted 07 September 2025