2. Academic Validation
  3. Rbbp7-mediated deacetylation of Acsl4 promotes ovarian aging by enhancing ferroptosis

Rbbp7-mediated deacetylation of Acsl4 promotes ovarian aging by enhancing ferroptosis

  • Int J Biol Macromol. 2025 Dec 30;339(Pt 2):149976. doi: 10.1016/j.ijbiomac.2025.149976.
Hongxu Chen 1,  Siyuan Wang 2,  Zhiming Ding 3,  Nie Zhang 1,  Jiaoyu Li 3,  Ruixin Zhang 1,  Xiaoying Liu 3,  Huifen Xiang 4,  Linghui Cheng 5,  Fei Zhong 6,  Fengyu Zhu 7
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, the First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei, 230022, Anhui, China; Department of Oncology, the Fifth Affiliated Hospital of Anhui Medical University, Fuyang, 236000, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No 218 Jixi Road, Hefei, 230022, Anhui, China.
  • 2 Department of Obstetrics and Gynecology, NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, the First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei, 230022, Anhui, China; Department of Oncology, the Fifth Affiliated Hospital of Anhui Medical University, Fuyang, 236000, China.
  • 3 Department of Obstetrics and Gynecology, NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, the First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei, 230022, Anhui, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No 218 Jixi Road, Hefei, 230022, Anhui, China.
  • 4 Department of Obstetrics and Gynecology, NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, the First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei, 230022, Anhui, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No 218 Jixi Road, Hefei, 230022, Anhui, China. Electronic address: [email protected].
  • 5 Department of Obstetrics and Gynecology, NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, the First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei, 230022, Anhui, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No 218 Jixi Road, Hefei, 230022, Anhui, China. Electronic address: [email protected].
  • 6 Department of Obstetrics and Gynecology, NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, the First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei, 230022, Anhui, China; Department of Oncology, the First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei, 230022, Anhui, China; Department of Oncology, the Fifth Affiliated Hospital of Anhui Medical University, Fuyang, 236000, China. Electronic address: [email protected].
  • 7 Department of Obstetrics and Gynecology, NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, the First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei, 230022, Anhui, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No 218 Jixi Road, Hefei, 230022, Anhui, China. Electronic address: [email protected].
PMID: 41478474 DOI: 10.1016/j.ijbiomac.2025.149976
Abstract

The ovarian aging can lead to infertility, increase risk of diabetes, heart disease, and Other serious problems. Ferroptosis is involved in the aging of various tissues. However, the mechanism underlying the role of Ferroptosis in natural ovarian aging remains unclear. Here, we revealed the role of Ferroptosis in ovarian aging and explore the intervention strategies for ovarian aging. Transcriptome data suggested that Ferroptosis may be involved in ovarian aging. Through iron ion detection, Prussian blue staining, immunohistochemistry (IHC) staining and western blot (WB), we further confirmed that Ferroptosis occurs in aging ovaries. Meanwhile, Acyl-CoA synthetase long-chain family member 4 (Acsl4) is highly expressed in senescent ovaries. We also found that the Ferroptosis inhibitor Deferoxamine (DFO), Ferrostatin-1 (Fer-1) or the Acsl4 inhibitor Rosiglitazone (Rosi) inhibited ovarian aging and granulosa cell damage in vivo and in vitro. Further mechanistic studies have shown that Myeloid ectopic viral integration site 2 (Meis2) could cooperate with specificity protein 1 (SP1) to promote transcription of Acsl4 gene. Acetyl-proteomic analysis demonstrated that the acetylation level of K401 residue in Acsl4 (Acsl4-K401) was significantly reduced, and retinoblastoma binding protein 7 (Rbbp7) was identified via immunoprecipitation-mass spectrometry (IP-MS) as a direct mediator of Acsl4 deacetylation. Deacetylation of Acsl4-K401 can increase enzyme activity by promoting ATP binding. In conclusion, the increased expression level and the decreased acetylation level of Acsl4 protein promote Ferroptosis, which in turn induces ovarian aging. Inhibiting Ferroptosis or Acsl4 can alleviate ovarian aging. Our research has revealed a new mechanism of ovarian aging and provided potential new targets for alleviating it.

Keywords

Acsl4 acetylation; Ferroptosis; Ovarian aging.

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