Gui Liming, Sun Jiajia, Zhong Qin, Liu Kan, Sun Qili, Di Yingtong, Picton Helen, Tang Bin, Hao Xiaojiang, Li Changzhong
Department of Obstetrics and Gynecology, Peking University Shenzhen Hospital, Shenzhen, China.
Institute of Obstetrics and Gynecology, Shenzhen Peking University-Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Shenzhen, China.
Commun Biol. 2025 Aug 1;8(1):1141. doi: 10.1038/s42003-025-08576-w.
Ovarian aging profoundly impacts reproductive health and accelerates the overall aging process, yet the development of effective therapeutic strategies remains a formidable challenge. In this study, we report the rejuvenating effects of HEP14, a natural activator of protein kinase C (PKC) pathway, on aged ovarian function by inducing mitophagy and effectively clearing reactive oxygen species. To ensure controlled and sustained delivery of HEP14 in vivo, we develop HEP14-loaded PLGA microspheres. Transcriptomic analysis reveals a significant overlap between the transcriptional profiles of HEP14-treated aged ovaries and those of adult ovaries, suggesting molecular rejuvenation process closely associated to HEP14-induced mitophagy. Histopathological evaluations further substantiate these findings, showing that HEP14 enhances mitophagy, exhibits antioxidative properties and promotes follicular regeneration. Consequently, ovarian endocrine function in aged mice is substantially restored. Using transmission electron microscopy, confocal microscopy, and western blot analysis alongside pharmocological inhibitors and PKC-specific siRNA, in vitro studies further demonstrate the restorative effect of HEP14 on mitophagy, leading to improved mitochondrial function and subsequent alleviation of oxidative stress in senescent ovarian granulosa cells. This effect is mediated through the activation of the PKC-ERK1/2 pathway, which plays an pivotal role in the action mechanism in HEP14. These discoveries offer new therapeutic hope for ovarian aging.
卵巢衰老对生殖健康产生深远影响，并加速整体衰老过程，然而开发有效的治疗策略仍然是一项艰巨的挑战。在本研究中，我们报告了蛋白激酶C（PKC）途径的天然激活剂HEP14通过诱导线粒体自噬并有效清除活性氧对衰老卵巢功能的恢复作用。为确保HEP14在体内的可控和持续递送，我们制备了负载HEP14的聚乳酸-羟基乙酸共聚物（PLGA）微球。转录组分析显示，HEP14处理的衰老卵巢与成年卵巢的转录谱之间存在显著重叠，表明分子恢复过程与HEP14诱导的线粒体自噬密切相关。组织病理学评估进一步证实了这些发现，表明HEP14增强线粒体自噬、具有抗氧化特性并促进卵泡再生。因此，老年小鼠的卵巢内分泌功能得到显著恢复。使用透射电子显微镜、共聚焦显微镜和蛋白质印迹分析，以及药理学抑制剂和PKC特异性小干扰RNA（siRNA），体外研究进一步证明了HEP14对线粒体自噬的恢复作用，从而改善了衰老卵巢颗粒细胞的线粒体功能并随后减轻了氧化应激。这种作用是通过激活PKC-ERK1/2途径介导的，该途径在HEP14的作用机制中起关键作用。这些发现为卵巢衰老提供了新的治疗希望。
