Jiang Yao, Shi Yonghua, Lv Meng, Wang Tao, Wang Penghao, Yuan Xiaolong, Gao Fei, Ma Bin
School of Medical, Molecular and Forensic Sciences, Murdoch University, Murdoch, WA, Australia.
Centre for Healthy Ageing, Health Futures Institute, Murdoch University, Murdoch, WA, Australia.
Cell Biol Toxicol. 2025 Sep 2;41(1):129. doi: 10.1007/s10565-025-10079-7.
Ovarian aging significantly contributes to the decline of the female reproductive system, adversely affecting fertility and endocrine homeostasis. To address the challenges posed by reproductive aging, natural products have shown promising preventive and therapeutic effects. Here, we investigated the beneficial effects of natural compound celastrol on ovarian development and aging, together with its underlying mechanisms. We found that celastrol administration at a concentration of 3 mg/kg promoted follicle development in young mice and enhanced porcine oocyte maturation, while regulating granulosa cell proliferation and apoptosis. In 12-month-old mice (equivalent to middle-aged adults), celastrol exhibited similar beneficial effects. Transcriptomic analysis revealed that differentially expressed genes post-celastrol treatment were associated with steroid biosynthesis, estrogen signaling pathways, type 2 diabetes, insulin secretion, meiosis, and apoptosis. Additionally, insulin receptor substrate 1 (IRS1), an adapter protein in insulin signaling, was shown to advance puberty in young mice and to facilitate oocyte maturation. Overexpression of IRS1 in oocytes promoted follicular development and oocyte maturation, resulting in enhanced steroid hormone levels, whereas IRS1 knockdown inhibited these processes. Our findings indicate that celastrol may regulate ovarian development and aging by modulating IRS1 expression and its related pathways, suggesting celastrol as a novel small-molecule compound targeting IRS1, and offering new perspectives for potential therapeutic strategies against reproductive aging and infertility.
卵巢衰老显著导致女性生殖系统衰退，对生育能力和内分泌稳态产生不利影响。为应对生殖衰老带来的挑战，天然产物已显示出有前景的预防和治疗效果。在此，我们研究了天然化合物雷公藤红素对卵巢发育和衰老的有益作用及其潜在机制。我们发现，以3mg/kg的浓度给予雷公藤红素可促进年轻小鼠的卵泡发育，增强猪卵母细胞成熟，同时调节颗粒细胞增殖和凋亡。在12月龄小鼠（相当于中年成年人）中，雷公藤红素也表现出类似的有益作用。转录组分析显示，雷公藤红素处理后差异表达的基因与类固醇生物合成、雌激素信号通路、2型糖尿病、胰岛素分泌、减数分裂和凋亡有关。此外，胰岛素受体底物1（IRS1）作为胰岛素信号中的衔接蛋白，被证明可促进年轻小鼠的青春期发育并促进卵母细胞成熟。卵母细胞中IRS1的过表达促进卵泡发育和卵母细胞成熟，导致类固醇激素水平升高，而IRS1的敲低则抑制这些过程。我们的研究结果表明，雷公藤红素可能通过调节IRS1表达及其相关途径来调节卵巢发育和衰老，这表明雷公藤红素是一种靶向IRS1的新型小分子化合物，并为针对生殖衰老和不孕症的潜在治疗策略提供了新的视角。
