2. Academic Validation
  3. Celastrol modulates IRS1 expression to alleviate ovarian aging and to enhance follicular development

Celastrol modulates IRS1 expression to alleviate ovarian aging and to enhance follicular development

  • Cell Biol Toxicol. 2025 Sep 2;41(1):129. doi: 10.1007/s10565-025-10079-7.
Yao Jiang 1 2,  Yonghua Shi 3,  Meng Lv 3 4,  Tao Wang 5,  Penghao Wang 1 6,  Xiaolong Yuan 1 2 3,  Fei Gao 7,  Bin Ma 8 9
Affiliations

Affiliations

  • 1 School of Medical, Molecular and Forensic Sciences, Murdoch University, Murdoch, WA, Australia.
  • 2 Centre for Healthy Ageing, Health Futures Institute, Murdoch University, Murdoch, WA, Australia.
  • 3 State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, Guangdong Laboratory of Lingnan Modern Agriculture, National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, Guangdong, China.
  • 4 Sun Yat-Sen University Cancer Center, Sun Yat-Sen University, Zhongshan, Guangdong, China.
  • 5 The Kids Research Institute Australia, Nedlands, WA, Australia.
  • 6 Centre for Crop and Food Innovation, Food Future Institute, Murdoch University, Murdoch, WA, Australia.
  • 7 Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Agricultural Genomics Institute at Shenzhen, Genome Analysis Laboratory of the Ministry of Agriculture, Chinese Academy of Agricultural Sciences, Shenzhen, Guangdong, China. gaofei01@caas.cn.
  • 8 School of Medical, Molecular and Forensic Sciences, Murdoch University, Murdoch, WA, Australia. B.Ma@murdoch.edu.au.
  • 9 Centre for Healthy Ageing, Health Futures Institute, Murdoch University, Murdoch, WA, Australia. B.Ma@murdoch.edu.au.
PMID: 40897829 DOI: 10.1007/s10565-025-10079-7
Abstract

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.

Keywords

Celastrol; Follicular development; IRS1; Natural product; Oocyte maturation; Ovarian aging.

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