2. Academic Validation
  3. Mevalonate metabolites boost aged oocyte quality through prenylation of small GTPases

Mevalonate metabolites boost aged oocyte quality through prenylation of small GTPases

  • Nat Aging. 2025 Aug 26. doi: 10.1038/s43587-025-00946-7.
Chuanming Liu # 1 2 3,  Huidan Zhang # 1 2 3,  Jialian Mao # 4,  Sainan Zhang # 5,  Xiao Tian 6,  Yibing Zhu 7,  Changjiang Wang 6,  Junshun Fang 1,  Huijie Pan 6,  Nannan Kang 1 2,  Yang Zhang 1 2,  Jidong Zhou 1 2,  Xin Zhen 1 2,  Guijun Yan 1 2,  Chaojun Li 5,  Yali Hu 1 2,  Cunqi Ye 7,  Ran Xie 6,  Chun So 8 9 10,  Haixiang Sun 11 12 13 14,  Lijun Ding 15 16 17 18 19 20 21
Affiliations

Affiliations

  • 1 Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 2 Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China.
  • 3 Jiangsu Human Reproductive Function Remodeling Engineering Research Center, Nanjing, China.
  • 4 Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
  • 5 State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, China.
  • 6 State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China.
  • 7 Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.
  • 8 National Institute of Biological Sciences, Beijing (NIBS), Beijing, China. sochun@nibs.ac.cn.
  • 9 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China. sochun@nibs.ac.cn.
  • 10 Assisted Reproductive Technology Unit, Department of Obstetrics and Gynecology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong. sochun@nibs.ac.cn.
  • 11 Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. stevensunz@163.com.
  • 12 Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China. stevensunz@163.com.
  • 13 Jiangsu Human Reproductive Function Remodeling Engineering Research Center, Nanjing, China. stevensunz@163.com.
  • 14 State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, China. stevensunz@163.com.
  • 15 Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. dinglijun@nju.edu.cn.
  • 16 Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China. dinglijun@nju.edu.cn.
  • 17 Jiangsu Human Reproductive Function Remodeling Engineering Research Center, Nanjing, China. dinglijun@nju.edu.cn.
  • 18 Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, China. dinglijun@nju.edu.cn.
  • 19 State Key Laboratory of Analytic Chemistry for Life Science, Nanjing University, Nanjing, China. dinglijun@nju.edu.cn.
  • 20 Clinical Center for Stem Cell Research, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China. dinglijun@nju.edu.cn.
  • 21 MOE Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing, China. dinglijun@nju.edu.cn.
  • # Contributed equally.
PMID: 40858817 DOI: 10.1038/s43587-025-00946-7
Abstract

Declining oocyte quality is the major contributor to female subfertility in aged mammals. Currently, there are no effective interventions to ameliorate aged oocyte quality. Here we found that oocytes at metaphase I from the cumulus-oocyte complexes of aged mice showed reduced cortical F-actin and lower levels of mevalonate (MVA) pathway metabolites, including MVA, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate. We further showed that MVA supplementation improved FPP levels, cortical F-actin and the quality of aged oocytes. Mechanistically, we found that MVA supplementation induced granulosa cells to synthesize FPP, which was subsequently transferred to aged oocytes. Transported FPP increased the prenylation of small GTPases, including CDC42 and RAC1, and promoted membrane localization of CDC42-N-WASP-Arp2/3 and RAC1-WAVE2-Arp2/3 complexes, promoting cortical F-actin reassembly and reducing aneuploidy of aged oocytes. We also identified a natural chemical compound, 8-isopentenyl flavone, with an isopentenyl side chain from Epimedium brevicornu Maxim, which could increase CDC42 and RAC1 prenylation, improving the cortical F-actin and the competence of aged oocytes, and ameliorating reproductive outcomes in aged female mice. Collectively, increasing the prenylation of small GTPases via MVA metabolites or 8-isopentenyl flavone provides a therapeutic approach for boosting female fertility during reproductive aging.

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