Zhang Yi-Piao, Dong Si-Mei, Li Zhi-Yuan, Zhou Cheng-Liang, Qiao Yun-Long, Xu Wan-Feng, Li Bo, Chu Chu, Lv Gui-Yuan, Chen Su-Hong
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, No. 18, Chaowang Road, Gongshu District, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China; Zhejiang Provincial Key Laboratory of TCM for Innovative R & D and Digital Intelligent Manufacturing of TCM Great Health Products, No. 1, Gongda Road, Deqing District, Zhejiang University of Technology, Huzhou, Zhejiang, 313200, China.
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, No. 18, Chaowang Road, Gongshu District, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China; Zhejiang Provincial Key Laboratory of TCM for Innovative R & D and Digital Intelligent Manufacturing of TCM Great Health Products, No. 1, Gongda Road, Deqing District, Zhejiang University of Technology, Huzhou, Zhejiang, 313200, China.
J Ethnopharmacol. 2025 Jul 4;352:120247. doi: 10.1016/j.jep.2025.120247.
Primary ovarian insufficiency (POI), which affects 3.7 % of women under age 40, is characterized by reduced ovarian function and infertility. Although Shoutai Pill (STW) is used for endocrine regulation, its mechanism in treating POI is unclear. Existing studies of POI have focused on ovarian damage, while the pathological changes in the uterus and its interactions with the ovary have not been clarified.
To uncover the mechanism by which STW alleviates POI through the regulation of internal reproductive organs (ovary-uterus axis).
We combined chemical profiling (UHPLC-Q-Exactive-MS/MS) with network pharmacology to identify STW's active ingredients and targets. A POI model was established in mice using tripterygium glycosides (TG). Mice were treated with STW (1.2, 2.4, or 3.6 g/kg) or a hormone-based positive control consisting of sequential administration of estradiol (0.15 mg/kg) and progesterone (1.5 mg/kg). Serum hormone levels (E2, FSH, LH), estrous cycles, and ovarian and uterine pathology were assessed. Proteomic changes were analyzed using data-independent acquisition (DIA) mass spectrometry, and the key findings were validated through molecular docking, immunohistochemistry, TUNEL, and western blotting.
STW contains 72 active compounds with good oral bioavailability (OB > 28 %). Key ingredients like luteolin and kaempferol were predicted to interact with POI-related genes (e.g., ESR1/2, EGFR, AKT1). In TG-induced POI mice, STW improved general health, rebalanced hormones, normalized estrous cycles, and promoted both follicular development and endometrial repair. Proteomic analysis and molecular docking supported that STW targets the EGFR/PI3K/AKT pathway. In vivo validation confirmed that STW activated this pathway, reducing pro-apoptotic BAX and increasing anti-apoptotic BCL2 in both the ovaries and uteri.
The results indicate that STW effectively restores hormonal homeostasis, ovarian function, and uterine morphology in POI mice. This therapeutic effect may involve inhibition of the ovarian-endometrial cell apoptosis cascade via activation of the EGFR/PI3K/AKT pathway. These findings provide new insights into the molecular mechanisms of POI and support STW as a potential therapeutic strategy targeting the ovary-uterus axis.
原发性卵巢功能不全（POI）影响40岁以下3.7%的女性，其特征为卵巢功能减退和不孕。尽管寿胎丸（STW）用于内分泌调节，但其治疗POI的机制尚不清楚。现有关于POI的研究主要集中在卵巢损伤方面，而子宫的病理变化及其与卵巢的相互作用尚未阐明。
揭示寿胎丸通过调节内生殖器官（卵巢-子宫轴）来缓解POI的机制。
我们将化学图谱分析（超高效液相色谱-四极杆-静电场轨道阱串联质谱法，UHPLC-Q-Exactive-MS/MS）与网络药理学相结合，以鉴定寿胎丸的活性成分和靶点。使用雷公藤多苷（TG）在小鼠中建立POI模型。小鼠分别接受寿胎丸（1.2、2.4或3.6 g/kg）或由雌二醇（0.15 mg/kg）和孕酮（1.5 mg/kg）序贯给药组成的激素阳性对照治疗。评估血清激素水平（E2、FSH、LH）、发情周期以及卵巢和子宫的病理学情况。使用数据非依赖采集（DIA）质谱法分析蛋白质组学变化，并通过分子对接、免疫组织化学、TUNEL和蛋白质印迹法对关键发现进行验证。
寿胎丸含有72种具有良好口服生物利用度（OB>28%）的活性化合物。预测木犀草素和山奈酚等关键成分与POI相关基因（如ESR1/2、EGFR、AKT1）相互作用。在TG诱导的POI小鼠中，寿胎丸改善了整体健康状况，重新平衡了激素水平，使发情周期正常化，并促进了卵泡发育和子宫内膜修复。蛋白质组学分析和分子对接支持寿胎丸靶向EGFR/PI3K/AKT通路。体内验证证实寿胎丸激活了该通路，减少了卵巢和子宫中促凋亡的BAX并增加了抗凋亡的BCL2。
结果表明寿胎丸能有效恢复POI小鼠的激素稳态、卵巢功能和子宫形态。这种治疗效果可能涉及通过激活EGFR/PI3K/AKT通路抑制卵巢-子宫内膜细胞凋亡级联反应。这些发现为POI的分子机制提供了新的见解，并支持寿胎丸作为一种针对卵巢-子宫轴的潜在治疗策略。
