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Cuproptosis-related gene CDKN2A as a molecular target for IPF diagnosis and therapeutics

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Abstract

Background

Idiopathic pulmonary fibrosis (IPF) is a progressive chronic interstitial lung disease with limited therapeutic options. Cuproptosis is a recently proposed novel form of programmed cell death, which has been strongly implicated in the development of various human diseases. However, the prognostic and therapeutic value of cuproptosis-related genes (CRGs) in IPF remains to be elucidated.

Methods

In the present study, weighted gene co-expression network analysis (WGCNA) was employed to identify the key CRGs associated with the development of IPF. The subsequent GSEA, immune cell correlation analysis, and single-cell RNA-Seq analysis were conducted to explore the potential role of the identified CRGs in IPF. In addition, ROC curves and survival analysis were used to assess the prognostic value of the key CRGs in IPF. Moreover, we explored the molecular mechanisms of participation of identified key CRGs in the development of pulmonary fibrogenesis through in vivo and in vitro experiments.

Results

The expression level of cyclin-dependent kinase inhibitor 2A (CDKN2A) is upregulated in the lung tissues of IPF patients and associated with disease severity. Notably, CDKN2A was constitutively expressed by fibrosis-promoting M2 macrophages. Decreased CDKN2A expression sensitizes M2 macrophages to elesclomol-induced cuproptosis in vitro. Inhibition of CDKN2A decreases the number of viable macrophages and attenuates bleomycin-induced pulmonary fibrosis in mice.

Conclusion

These findings indicate that CDKN2A mediates the resistance of fibrosis-promoting M2 macrophages to cuproptosis and promotes pulmonary fibrosis in mice. Our work provides fresh insights into CRGs in IPF with potential value for research in the pathogenesis, diagnosis, and a new therapy strategy for IPF.

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Data availability

The data that support this study are available within the article and its Supplementary data files or available from the authors upon request.

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Acknowledgements

This work was supported by the Jiangsu Provincial Double-Innovation Doctor Program and Jiangsu Key Discipline Fund for the 14th Five-Year Plan (Biology).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, School of Medicine and Holistic Integrative Medicine, Jiangsu Collaborative Innovation Canter of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Baowen Xu, Kaiyong Yang, Xin Han & Jiwei Hou

  2. Immunology and Reproduction Biology Laboratory and State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, 210093, China

    Jiwei Hou

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Contributions

Conceptualization, B.X. and K.Y.; methodology and formal analysis, B.X., K.Y., L.L., X.H., and J.H.; original draft preparation, B.X. and K.Y.; writing—review and editing, X.H. and J.H.; funding acquisition, X.H. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Jiwei Hou.

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All animal procedures were approved by the Animal Care and Use Committee of Nanjing University under the animal protocol number SYXK (Su) 2009–0017.

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Xu, B., Yang, K., Han, X. et al. Cuproptosis-related gene CDKN2A as a molecular target for IPF diagnosis and therapeutics. Inflamm. Res. 72, 1147–1160 (2023). https://doi.org/10.1007/s00011-023-01739-7

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  • DOI: https://doi.org/10.1007/s00011-023-01739-7

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