Yang Hongyu, Chen Shichao, Yin Shanshan, Ding Qi
Department of Obstetrics and Gynecology, Bethune International Peace Hospital, Shijiazhuang, Hebei Province, China.
J Appl Toxicol. 2025 Feb;45(2):256-265. doi: 10.1002/jat.4697. Epub 2024 Sep 16.
Polycystic ovary syndrome (PCOS) is a common endocrine disorder that can cause menstrual irregularities, infertility, polycystic ovaries, and metabolic abnormalities. Female reproductive health and quality of life are significantly affected by PCOS, which has recently been associated with ferroptosis in granulosa cells (GCs). Nuciferine (NF) is a naturally extracted substance with multiple pharmacological activities, which is reported with anti-ferroptosis function. Herein, the influence of NF for androgen-induced ferroptosis in GCs was investigated to explore the potential value of NF on treating PCOS. 10 μM NF and 20 μM NF were employed for treating KGN cells according to cell viability results. KGN cells were treated with 10 μM dehydroepiandrosterone (DHEA) for 1 day, followed by introducing 10 μM NF and 20 μM NF for 24 h. Strikingly reduced cell viability, increased lactate dehydrogenase release and reactive oxygen species (ROS) production, enhanced apoptosis, upregulated Bax, downregulated Bcl-2, restrained malondialdehyde contents, and declined superoxide dismutase activity were observed in DHEA-treated KGN cells, which were significantly reversed by NF. Significantly repressed GPX4, SLC7A11, and SOX2 levels, as well as increased ACSL4 levels and Fe levels in DHEA-treated KGN cells, were notably rescued by NF. Furthermore, the inhibitory effect of NF on ROS production and ferroptosis in DHEA-treated KGN cells was partially abrogated by silencing SOX2. Collectively, NF protected DHEA-injured ovarian GCs by inhibiting ferroptosis via upregulating SOX2.
多囊卵巢综合征（PCOS）是一种常见的内分泌紊乱疾病，可导致月经不调、不孕、多囊卵巢和代谢异常。PCOS对女性生殖健康和生活质量有显著影响，最近发现其与颗粒细胞（GCs）的铁死亡有关。荷叶碱（NF）是一种具有多种药理活性的天然提取物，有抗铁死亡功能的报道。在此，研究了NF对雄激素诱导的GCs铁死亡的影响，以探索NF在治疗PCOS方面的潜在价值。根据细胞活力结果，用10μM NF和20μM NF处理KGN细胞。用10μM脱氢表雄酮（DHEA）处理KGN细胞1天，然后加入10μM NF和20μM NF处理24小时。在DHEA处理的KGN细胞中观察到细胞活力显著降低、乳酸脱氢酶释放增加和活性氧（ROS）生成增加、凋亡增强、Bax上调、Bcl-2下调、丙二醛含量受到抑制以及超氧化物歧化酶活性下降，而NF可显著逆转这些变化。NF显著挽救了DHEA处理的KGN细胞中显著受抑制的GPX4、SLC7A11和SOX2水平，以及增加的ACSL4水平和铁水平。此外，沉默SOX2可部分消除NF对DHEA处理的KGN细胞中ROS生成和铁死亡的抑制作用。总体而言，NF通过上调SOX2抑制铁死亡，从而保护DHEA损伤的卵巢GCs。
