2. Academic Validation
  3. Decreased PTGES2 Farnesylation in Granulosa Cells Compromises PGE2-Dependent Cumulus Expansion and Oocyte Maturation During Ovarian Aging

Decreased PTGES2 Farnesylation in Granulosa Cells Compromises PGE2-Dependent Cumulus Expansion and Oocyte Maturation During Ovarian Aging

  • Aging Cell. 2026 Feb;25(2):e70374. doi: 10.1111/acel.70374.
Sainan Zhang 1 2,  Jiahui Qi 1,  Chuanming Liu 3,  Huidan Zhang 3,  Bichun Guo 3,  Die Wu 3,  Yicen Liu 4,  Xin Zhen 3,  Yang Zhang 3,  Nannan Kang 3,  Jidong Zhou 3,  Guijun Yan 3,  Chaojun Li 1,  Lijun Ding 1 2 3 4 5 6 7 8,  Haixiang Sun 1 2 3 5 6
Affiliations

Affiliations

  • 1 Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China.
  • 2 State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, China.
  • 3 Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 4 Center for Reproductive Medicine and Obstetrics and Gynecology, Joint Institute of Nanjing Drum Tower Hospital for Life and Health, College of Life Science, Nanjing Normal University, Nanjing, China.
  • 5 Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China.
  • 6 Jiangsu Human Reproductive Function Remodeling Engineering Research Center, Nanjing, China.
  • 7 Clinical Center for Stem Cell Research, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China.
  • 8 State Key Laboratory of Analytic Chemistry for Life Science, Nanjing University, Nanjing, China.
PMID: 41521701 DOI: 10.1111/acel.70374
Abstract

With the increasing trend of delayed childbearing, the decline in oocyte quality associated with advanced maternal age has emerged as a pressing concern. However, the mechanism remains unclear, and effective strategies for improvement are currently lacking. Previously, we reported that the downregulation of the mevalonate pathway in aged granulosa cells (GCs) contributed to meiotic defects in oocytes, which may implicate farnesyl pyrophosphate-mediated protein farnesylation. Nevertheless, the role of farnesylation in ovarian aging and its impact on oocytes requires further investigation. In this study, using cumulus-oocyte complexes (COCs) from young and aged female mice, we observed impaired cumulus expansion and concurrent meiotic defects during aged oocyte maturation, accompanied by significantly reduced protein farnesylation in aged GCs. Furthermore, inhibiting farnesylation with FTI-277 in young COCs recapitulated the aging phenotype, disrupting cumulus expansion and inducing meiotic defects similar to those in aged COCs. Conversely, restoring farnesylation via farnesol supplementation effectively ameliorated these deficits in both aged COCs (in vitro) and aged mice (in vivo). Proteomic analysis and experimental validation identified prostaglandin E2 synthase 2 (PTGES2) as a farnesylated protein. Mechanistically, age-related decline in PTGES2 farnesylation in GCs reduces its endoplasmic reticulum localization and impairs prostaglandin E2 (PGE2) production, thereby compromising PGE2-dependent cumulus expansion and oocyte maturation. Collectively, our findings highlight the detrimental effects of decreased farnesylation in aged GCs on oocyte quality and propose a potential therapeutic strategy for improving the developmental competence of aged oocytes.

Keywords

PTGES2; cumulus expansion; farnesylation; oocyte maturation; ovarian aging.

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