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

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..

Medienart:

E-Artikel

Erscheinungsjahr:

2023

Erschienen:

2023

Enthalten in:

Zur Gesamtaufnahme - volume:72

Enthalten in:

Inflammation research - 72(2023), 6 vom: 11. Mai, Seite 1147-1160

Sprache:

Englisch

Beteiligte Personen:

Xu, Baowen [VerfasserIn]
Yang, Kaiyong [VerfasserIn]
Han, Xin [VerfasserIn]
Hou, Jiwei [VerfasserIn]

Links:

Volltext [lizenzpflichtig]

Themen:

Cuproptosis
Cyclin-dependent kinase inhibitor 2A
Idiopathic pulmonary fibrosis
Macrophages

Anmerkungen:

© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

doi:

10.1007/s00011-023-01739-7

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

OLC2143954328

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