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N6-Methyladenosine-modified circSAV1 triggers ferroptosis in COPD through recruiting YTHDF1 to facilitate the translation of IREB2

Cell Death & Differentiation volume 30, pages 1293–1304 (2023)Cite this article

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Abstract

Epithelial cell damage-initiated chronic obstructive pulmonary disease (COPD) is implicated in regulated cell death (RCD) including ferroptosis triggered by complex gene-environment interactions. Our data showed that iron overload and ferroptosis are associated with COPD progression in COPD patients and in experimental COPD. Furthermore, we found that, in lung tissues of COPD patients, circSAV1 was associated with COPD progression by circRNA-seq screening. Knockdown of circSAV1 reversed cigarette smoke extract (CSE)-induced ferroptosis. Mechanistically, m6A-modified circSAV1 formed an RNA-protein ternary complex of circSAV1/YTHDF1/IREB2 to facilitate the translation of IREB2 mRNA. Elevated protein levels of IREB2 disrupted iron homeostasis, resulting in accumulation of a labile iron pool (LIP) and lipid peroxidation, which contribute to ferroptosis. Here we demonstrate, by use of an experimental COPD model induced by cigarette smoke (CS), that silencing of circSAV1 and the treatment with deferoxamine (DFO) blocked CS-induced ferroptosis of lung epithelial cells, which attenuated COPD progression in mice. Our results reveal that N6-methyladenosine-modified circSAV1 triggers ferroptosis in COPD through recruiting YTHDF1 to facilitate the translation of IREB2, indicating that circSAV1 is a mediator of ferroptosis and that circSAV1-dependent ferroptosis is a therapeutic target for COPD.

In lung epithelial cell, m6A-modified circSAV1, via recruiting YTHDF1, induces the formation of a circSAV1/YTHDF1/IREB2 mRNA protein ternary complex, which promotes translation of IREB2 mRNA. Further, elevated IREB2 contributes to the accumulation of a labile iron pool (LIP) and lipid peroxidation, then triggers ferroptosis of lung epithelial cells. The ferroptosis of airway epithelial cells and alveolar epithelial cells induces airway remodeling and emphysema, respectively, which causes COPD.

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Fig. 1: Ferroptosis, an iron homeostasis disorder, relates to COPD progression.
Fig. 2: circSAV1 was elevated in lung tissue of smokers and COPD smokers, and related to COPD progression.
Fig. 3: circSAV1 enhances free iron and triggers ferroptosis in CSE-treated BEAS-2B cells.
Fig. 4: circSAV1 interacts with YTHDF1 via its m6A motif, which contributes to IREB2 mRNA translation.
Fig. 5: In BEAS-2B cells, circSAV1 triggers ferroptosis via IREB2.
Fig. 6: DFO ameliorates emphysema and airway remodeling through inhibiting ferroptosis in experimental COPD.
Fig. 7: Downregulated circSAV1 reduces emphysema and airway remodeling through inhibiting ferroptosis in experimental COPD.

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Data availability

The data that support the findings of this study are available from the corresponding authors on reasonable request.

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Acknowledgements

The authors thank Donald L. Hill (University of Alabama at Birmingham, USA), an experienced, English-speaking scientific editor, for editing. This work was supported by the Natural Science Foundations of China (81973085, 82173472, 82173563, 81973005); and the Priority Academic Program Development of Jiangsu Higher Education Institutions (2022); and the Top Talent Support Program for young and middle-aged people of Wuxi Health Committee (BJ2020006).

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Author notes

  1. These authors contributed equally: Haibo Xia, Yan Wu, Jing Zhao.

Authors and Affiliations

  1. Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute of Public Health, Gusu School, Nanjing Medical University, Nanjing, 211166, Jiangsu, People’s Republic of China

    Haibo Xia, Jing Zhao, Cheng Cheng, Jiaheng Lin, Yi Yang, Lu Lu & Qizhan Liu

  2. School of Public Health, Southeast University, Nanjing, 210096, Jiangsu, People’s Republic of China

    Haibo Xia & Qizhan Liu

  3. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People’s Republic of China

    Haibo Xia, Cheng Cheng, Jiaheng Lin, Yi Yang & Qizhan Liu

  4. Department of Respiratory and Critical Care Medicine, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, Jiangsu, People’s Republic of China

    Yan Wu & Tao Bian

  5. Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, 210009, Jiangsu, People’s Republic of China

    Jing Zhao & Quanyong Xiang

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Contributions

QL and TB developed the hypothesis. TB and YW provided the clinical samples. HX, YW and JL performed the RNA-seq. HX, JZ, JL, CC, YY, LL and QX performed the in vivo experiments. HX, JZ and CC performed the in vitro experiments. QL and HX wrote the manuscript.

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Correspondence to Tao Bian or Qizhan Liu.

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All human research was approved by the ethical committee of Nanjing Medical University (number: 2021-130). All experiments with animals were reviewed and approved by the animal ethics committee of Nanjing Medical University (IACUC-1907025).

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Xia, H., Wu, Y., Zhao, J. et al. N6-Methyladenosine-modified circSAV1 triggers ferroptosis in COPD through recruiting YTHDF1 to facilitate the translation of IREB2. Cell Death Differ 30, 1293–1304 (2023). https://doi.org/10.1038/s41418-023-01138-9

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