Zhou Qi, Ouyang Xiaoling, Tang Hong, Wang Yongfeng, Hua Yu, Li Linxia
Departments of Gynaecology and Obstetrics, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China; Central Laboratory, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China.
Departments of Gynaecology and Obstetrics, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China.
Int Immunopharmacol. 2025 Jan 27;146:113817. doi: 10.1016/j.intimp.2024.113817. Epub 2024 Dec 25.
Polycystic ovary syndrome (PCOS) is a common endocrine disorder, and its close relationship with oxidative stress has been well-documented. Atractylodin (ATR) plays a role in the treatment of many diseases through its antioxidant function. However, its function in PCOS remains unexplored. In this study, the function and underlying mechanisms of ATR in mitigating PCOS symptoms were investigated.
A mouse model of PCOS induced using DHEA and a high-fat diet was established, and many factors such as hormone levels (FSH, LH, testosterone, and progesterone), the estrous cycle, and ovarian shape were evaluated. In vitro, PCOS model was established by DHEA-induced KGN cell, and the effects of ATR on ferroptosis and oxidative stress markers were explored. Specifically, the viability of KGN cells treated with ATR was assessed using the CCK-8 assay, and the levels of malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) were measured to evaluate oxidative stress. Expression of ferroptosis-related genes (NRF2, GPX4, SLC7A11) and PDK4 was analyzed by qRT-PCR and Western blotting. PDK4's interaction with ATR was examined through molecular docking and confirmed by surface plasmon resonance (SPR) analysis.
Our data show that the treatment of ATR markedly increased hormone levels and improved normal estrous cycles. Moreover, ATR was found to improve ovarian morphology by decreasing cystic dilatation and increasing the number of corpora lutea. Mechanistically, our research found that ATR regulates the expression of PDK4 by binding to its GLY331 and inhibits granulosa cell ferroptosis by regulating the JAK-STAT3 pathway mediated by PDK4.
In conclusion, our study suggest that ATR may be a therapeutic option for managing PCOS and PDK4 could be a target for the development of new drugs for PCOS.
多囊卵巢综合征（PCOS）是一种常见的内分泌紊乱疾病，其与氧化应激的密切关系已得到充分证明。白术内酯（ATR）通过其抗氧化功能在多种疾病的治疗中发挥作用。然而，其在PCOS中的作用仍未被探索。在本研究中，研究了ATR减轻PCOS症状的功能及潜在机制。
建立了用脱氢表雄酮（DHEA）和高脂饮食诱导的PCOS小鼠模型，并评估了激素水平（促卵泡生成素、促黄体生成素、睾酮和孕酮）、发情周期和卵巢形态等多种因素。在体外，用DHEA诱导KGN细胞建立PCOS模型，探讨ATR对铁死亡和氧化应激标志物的影响。具体而言，使用CCK-8法评估用ATR处理的KGN细胞的活力，并测量丙二醛（MDA）、谷胱甘肽（GSH）和活性氧（ROS）水平以评估氧化应激。通过qRT-PCR和蛋白质印迹法分析铁死亡相关基因（NRF2、GPX4、SLC7A11）和PDK4的表达。通过分子对接研究PDK4与ATR的相互作用，并通过表面等离子体共振（SPR）分析进行确认。
我们的数据表明，ATR治疗显著提高了激素水平并改善了正常发情周期。此外，发现ATR通过减少囊性扩张和增加黄体数量来改善卵巢形态。从机制上讲，我们的研究发现ATR通过与PDK4的GLY331结合来调节其表达，并通过调节由PDK4介导的JAK-STAT3途径抑制颗粒细胞铁死亡。
总之，我们的研究表明，ATR可能是治疗PCOS的一种选择，而PDK4可能是开发PCOS新药的靶点。
