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Inhibition of ferroptosis counteracts the advanced maternal age-induced oocyte deterioration

Cell Death & Differentiation volume 32, pages 1071–1085 (2025)Cite this article

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A Correction to this article was published on 09 May 2025

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Abstract

Ferroptosis, a recently discovered form of programmed cell death triggered by the excessive accumulation of iron-dependent lipid peroxidation products, plays a critical role in the development of various diseases. However, whether it is involved in the age-related decline in oocyte quality remains unexplored. Here, we took advantage of nano-proteomics to uncover that reduced ferritin heavy chain (Fth1) level is a major cause leading to the occurrence of ferroptosis in aged oocytes. Specifically, induction of ferroptosis in young oocytes by its activators RSL3 and FAC, or knockdown of Fth1 all phenocopied the meiotic defects observed in aged oocytes, including failed oocyte meiotic maturation, aberrant cytoskeleton dynamics, as well as impaired mitochondrial function. Transcriptome analysis showed that knockdown of Fth1 affected meiosis-related and aging-related pathways in oocytes. Conversely, inhibition of ferroptosis by its inhibitors or expression of Fth1 improved the quality of aged oocytes. We also validated the effects of ferroptosis on the porcine oocyte quality in vitro. Altogether, we demonstrate the contribution of ferroptosis to the age-induced oocyte defects and evidence that inhibition of ferroptosis might be a feasible strategy to ameliorate the reproductive outcomes of female animals at an advanced age.

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Fig. 1: Identification of ferroptosis pathway enriched in aged oocytes by nano-proteomics.
Fig. 2: Induction of ferroptosis in young oocytes by RSL3 treatment.
Fig. 3: Effects of RSL3 treatment on the quality of young oocytes.
Fig. 4: Induction of ferroptosis in young oocytes by Fth1 knockdown.
Fig. 5: Effects of Fth1 knockdown on the quality of young oocytes.
Fig. 6: Effects of Fth1 knockdown on the transcriptome profile in young oocytes.
Fig. 7: Effects of exogenous expression of Fth1 in aged oocytes on the ferroptosis and oocyte maturation.
Fig. 8: Effects of lipro-1 administration in aged mice on the oocyte ferroptosis and quality.
Fig. 9: Effects of VE supplementation on the quality of porcine oocytes treated with RSL3.

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Data availability

All study data are included in the article and supplementary information. Data supporting the findings of this study are available on reasonable request from the corresponding author.

Change history

  • 25 April 2025

    The original online version of this article was revised: Since the publication of this article, the authors have noticed that the images in Figure 5c (Control panel) were mixed up with those in Figure S2a (RSL3+DFO panel) due to the unintentional errors during manuscript preparation. The corrected Figure 5 is shown below. The correction does not alter the findings and conclusions of the original published study.

  • 09 May 2025

    A Correction to this paper has been published: https://doi.org/10.1038/s41418-025-01519-2

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Funding

This work was supported by the National Key Research and Development Program of China (2023YFD1300502), and the National Natural Science Foundation of China (U24A20437).

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  1. These authors contributed equally: Wenjun Zeng, Feixue Wang.

Authors and Affiliations

  1. College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China

    Wenjun Zeng, Feixue Wang, Zhaokang Cui, Yu Li, Na Li, Zipeng Mao, Hanwen Zhang, Yiting Liu, Yilong Miao, Shaochen Sun, Yafei Cai & Bo Xiong

  2. College of Animal Sciences, Zhejiang University, Hangzhou, China

    Yu Zhang & Bo Xiong

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Contributions

WZ performed the experiments, analyzed the data, and wrote the manuscript; FW performed the experiments; ZC performed the experiments; YZ performed the experiments; YL performed the experiments; NL performed the experiments; ZM performed the experiments; HZ performed the experiments; YL performed the experiments; YM performed the experiments; SS analyzed the data; YC analyzed the data; BX designed the research, analyzed the data, and wrote the manuscript.

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Correspondence to Bo Xiong.

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All mouse protocols and experimental procedures were approved by the Animal Research Institute Committee of Nanjing Agricultural University, China.

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The original online version of this article was revised: Since the publication of this article, the authors have noticed that the images in Figure 5c (Control panel) were mixed up with those in Figure S2a (RSL3+DFO panel) due to the unintentional errors during manuscript preparation. The corrected Figure 5 is shown below. The correction does not alter the findings and conclusions of the original published study.

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Zeng, W., Wang, F., Cui, Z. et al. Inhibition of ferroptosis counteracts the advanced maternal age-induced oocyte deterioration. Cell Death Differ 32, 1071–1085 (2025). https://doi.org/10.1038/s41418-025-01456-0

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