HEP14 treatment improves ovarian function in aged mice through mitophagy enhancement and oxidative stress reduction
Abstract 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) p...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-08-01
|
| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08576-w |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849225989630984192 |
|---|---|
| author | Liming Gui Jiajia Sun Qin Zhong Kan Liu Qili Sun Yingtong Di Helen Picton Bin Tang Xiaojiang Hao Changzhong Li |
| author_facet | Liming Gui Jiajia Sun Qin Zhong Kan Liu Qili Sun Yingtong Di Helen Picton Bin Tang Xiaojiang Hao Changzhong Li |
| author_sort | Liming Gui |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-6841663aa4f248e5b4f6118fc015d607 |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-6841663aa4f248e5b4f6118fc015d6072025-08-24T11:46:20ZengNature PortfolioCommunications Biology2399-36422025-08-018111910.1038/s42003-025-08576-wHEP14 treatment improves ovarian function in aged mice through mitophagy enhancement and oxidative stress reductionLiming Gui0Jiajia Sun1Qin Zhong2Kan Liu3Qili Sun4Yingtong Di5Helen Picton6Bin Tang7Xiaojiang Hao8Changzhong Li9Department of Obstetrics and Gynecology, Peking University Shenzhen HospitalDepartment of Obstetrics and Gynecology, Peking University Shenzhen HospitalCentre for Tissue Engineering and Stem Cell Research, Guizhou Medical UniversityDepartment of Obstetrics and Gynecology, Peking University Shenzhen HospitalDepartment of Biomedical Engineering, Southern University of Science and TechnologyState Key Laboratory of Phytochemistry and Plant Resource in West China, Kunming Institute of Botany, Chinese Academy of SciencesReproduction and Early Development Research Group, Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of LeedsDepartment of Biomedical Engineering, Southern University of Science and TechnologyState Key Laboratory of Phytochemistry and Plant Resource in West China, Kunming Institute of Botany, Chinese Academy of SciencesDepartment of Obstetrics and Gynecology, Peking University Shenzhen HospitalAbstract 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.https://doi.org/10.1038/s42003-025-08576-w |
| spellingShingle | Liming Gui Jiajia Sun Qin Zhong Kan Liu Qili Sun Yingtong Di Helen Picton Bin Tang Xiaojiang Hao Changzhong Li HEP14 treatment improves ovarian function in aged mice through mitophagy enhancement and oxidative stress reduction Communications Biology |
| title | HEP14 treatment improves ovarian function in aged mice through mitophagy enhancement and oxidative stress reduction |
| title_full | HEP14 treatment improves ovarian function in aged mice through mitophagy enhancement and oxidative stress reduction |
| title_fullStr | HEP14 treatment improves ovarian function in aged mice through mitophagy enhancement and oxidative stress reduction |
| title_full_unstemmed | HEP14 treatment improves ovarian function in aged mice through mitophagy enhancement and oxidative stress reduction |
| title_short | HEP14 treatment improves ovarian function in aged mice through mitophagy enhancement and oxidative stress reduction |
| title_sort | hep14 treatment improves ovarian function in aged mice through mitophagy enhancement and oxidative stress reduction |
| url | https://doi.org/10.1038/s42003-025-08576-w |
| work_keys_str_mv | AT liminggui hep14treatmentimprovesovarianfunctioninagedmicethroughmitophagyenhancementandoxidativestressreduction AT jiajiasun hep14treatmentimprovesovarianfunctioninagedmicethroughmitophagyenhancementandoxidativestressreduction AT qinzhong hep14treatmentimprovesovarianfunctioninagedmicethroughmitophagyenhancementandoxidativestressreduction AT kanliu hep14treatmentimprovesovarianfunctioninagedmicethroughmitophagyenhancementandoxidativestressreduction AT qilisun hep14treatmentimprovesovarianfunctioninagedmicethroughmitophagyenhancementandoxidativestressreduction AT yingtongdi hep14treatmentimprovesovarianfunctioninagedmicethroughmitophagyenhancementandoxidativestressreduction AT helenpicton hep14treatmentimprovesovarianfunctioninagedmicethroughmitophagyenhancementandoxidativestressreduction AT bintang hep14treatmentimprovesovarianfunctioninagedmicethroughmitophagyenhancementandoxidativestressreduction AT xiaojianghao hep14treatmentimprovesovarianfunctioninagedmicethroughmitophagyenhancementandoxidativestressreduction AT changzhongli hep14treatmentimprovesovarianfunctioninagedmicethroughmitophagyenhancementandoxidativestressreduction |