Polycystic ovary syndrome (PCOS), a prevalent reproductive disorder in women of reproductive age, features androgen excess, ovulatory dysfunction, and polycystic ovaries. Despite its high prevalence, specific pharmacologic intervention for PCOS is challenging. In this study, we identified artemisinins as anti-PCOS agents. Our finding demonstrated the efficacy of artemisinin derivatives in alleviating PCOS symptoms in both rodent models and human patients, curbing hyperandrogenemia through suppression of ovarian androgen synthesis. Artemisinins promoted cytochrome P450 family 11 subfamily A member 1 (CYP11A1) protein degradation to block androgen overproduction. Mechanistically, artemisinins directly targeted lon peptidase 1 (LONP1), enhanced LONP1-CYP11A1 interaction, and facilitated LONP1-catalyzed CYP11A1 degradation. Overexpression of LONP1 replicated the androgen-lowering effect of artemisinins. Our data suggest that artemisinin application is a promising approach for treating PCOS and highlight the crucial role of the LONP1-CYP11A1 interaction in controlling hyperandrogenism and PCOS occurrence.

中文翻译：

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青蒿素通过介导 LONP1-CYP11A1 相互作用改善多囊卵巢综合征


多囊卵巢综合症（PCOS）是育龄妇女中常见的一种生殖疾病，其特征是雄激素过多、排卵功能障碍和多囊卵巢。尽管多囊卵巢综合症的患病率很高，但针对多囊卵巢综合症的具体药物干预仍具有挑战性。在这项研究中，我们将青蒿素确定为抗多囊卵巢综合症药物。我们的研究结果证明了青蒿素衍生物在缓解啮齿类动物模型和人类患者的多囊卵巢综合症症状方面的功效，通过抑制卵巢雄激素合成来抑制高雄激素血症。青蒿素促进细胞色素 P450 家族 11 亚家族 A 成员 1 (CYP11A1) 蛋白降解，从而阻止雄激素过量产生。从机制上讲，青蒿素直接靶向 lon 肽酶 1 (LONP1)，增强 LONP1-CYP11A1 相互作用，并促进 LONP1 催化的 CYP11A1 降解。 LONP1 的过度表达复制了青蒿素的雄激素降低作用。我们的数据表明，青蒿素应用是治疗 PCOS 的一种有前景的方法，并强调了 LONP1-CYP11A1 相互作用在控制高雄激素血症和 PCOS 发生中的关键作用。