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  3. Rescuing fertility: Itaconic acid prevents ovarian damage through NRF2-mediated pyroptosis pathways in diminished ovarian reserve models

Rescuing fertility: Itaconic acid prevents ovarian damage through NRF2-mediated pyroptosis pathways in diminished ovarian reserve models

  • Cell Signal. 2025 Jul:131:111766. doi: 10.1016/j.cellsig.2025.111766.
Ling Yang 1,  Wenya Mo 2,  Lei Xin 3,  Mingzhao Zhang 4,  Kegong Chen 5,  Xiaohui Guo 6,  Jing Zhang 7,  Biao Yu 8
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, the Hexian People's Hospital, Maanshan 238200, Anhui, China.
  • 2 School of Nursing, Anhui Medical University, Hefei 230032, Anhui, China; Department of Urology, the First Affiliated Hospital of University of Science and Technology of China, Hefei 230036, Anhui, China.
  • 3 Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, Anhui, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, Hefei 230032, Anhui, China.
  • 4 Department of Breast Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China.
  • 5 Department of Thoracic Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China.
  • 6 Department of Pathology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China. Electronic address: 514253129@qq.com.
  • 7 College of Veterinary Medicine, Jilin University, Changchun 130062, Jilin, China. Electronic address: c16604463475@163.com.
  • 8 Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, Anhui, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, Hefei 230032, Anhui, China. Electronic address: biaoyu@ahmu.edu.cn.
PMID: 40147551 DOI: 10.1016/j.cellsig.2025.111766
Abstract

Background: Diminished ovarian reserve (DOR) is a major cause of infertility, often triggered by inflammation and oxidative stress. Pyroptosis, a form of programmed cell death, has been implicated in DOR pathogenesis. Itaconic acid (IA), an Endogenous Metabolite, is known for its anti-inflammatory and antioxidant properties. This study aimed to explore whether IA could alleviate lipopolysaccharide (LPS)-induced DOR in mice by inhibiting Pyroptosis through the NRF2 pathway.

Methods: A DOR mouse model was established by administering LPS for 5 consecutive days, followed by IA treatment. Ovarian function was assessed by follicle count and hormone levels. Inflammatory markers, oxidative stress, and pyroptosis-related proteins were evaluated in both in vivo and in vitro models. The molecular mechanism was further investigated using inhibitors and molecular docking studies.

Results: IA significantly improved ovarian function in LPS-induced DOR mice by increasing the number of follicles and normalizing hormone levels. IA also reduced inflammation, oxidative stress, and Pyroptosis, as evidenced by lower expression of NLRP3, cleaved-caspase-1, and N-GSDMD, while increasing NRF2 expression. In vitro, IA enhanced granulosa cell (GC) viability, reduced Reactive Oxygen Species (ROS), and decreased Pyroptosis in LPS-treated GCs. Additionally, the beneficial effects of IA were mediated via the NRF2 pathway, as NRF2 inhibition (ML385) reversed these improvements. Additionally, we identified GSDMD as a downstream target of IA, with inhibition of GSDMD ameliorating DOR progression and inflammatory responses.

Conclusion: IA alleviates LPS-induced DOR by reducing inflammation, oxidative stress, and Pyroptosis through activation of the NRF2 signaling and direct inhibition of the GSDMD pathway. These findings suggest that IA may serve as a potential therapeutic agent for improving ovarian reserve and fertility.

Keywords

Diminished ovarian reserve (DOR); Granulosa cells (GCs); Inflammation; Itaconic acid (IA); Oxidative stress; Pyroptosis.

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