Nuclear protein 1 is a cell death regulator in primary human airway epithelial cells and reduced in idiopathic pulmonary fibrosis
The airway epithelium is the first site of injury from cigarette smoke (CS), a major risk factor for chronic lung disease including idiopathic pulmonary fibrosis (IPF). Here, we report the first intracellular proteomic analysis of CS exposure in fully differentiated primary human bronchial epithelial cells (phBECs). Following pathway enrichment analysis, we identified nuclear protein 1 (NUPR1) as a candidate regulator of epithelial stress responses. In contrast to the prediction by pathway enrichment analysis, NUPR1 activity was not altered by CS in vitro. Nevertheless, inhibition of its nuclear translocation using ZZW-115 revealed a cytoprotective and anti-apoptotic role in phBECs, as demonstrated by increased apoptosis and impaired epithelial integrity. NUPR1 expression was markedly reduced in IPF whole lung tissue and bronchial epithelium. IPF-derived basal cells differentiated into an epithelium exhibiting fewer ciliated and more secretory cells which exhibited significantly higher sensitivity to NUPR1 inhibition. Our findings underscore cell type- and tissue-specific variation in NUPR1-dependent pathways. Collectively, this study positions NUPR1 as a context-dependent epithelial stress regulator whose loss may contribute to epithelial vulnerability in IPF.
Authors
- Misako Nakayama (ORCID: https://orcid.org/0000-0001-8611-0662)
- Anne Hilgendorff (ORCID: https://orcid.org/0000-0002-3725-996X)
- Juliane Merl‐Pham (ORCID: https://orcid.org/0000-0002-3422-4083)
- Elisabeth Dick
- Patricia Santofimia‐Castaño (ORCID: https://orcid.org/0000-0003-2506-5567)
- Ashesh Chakraborty
- Stefanie M. Hauck (ORCID: https://orcid.org/0000-0002-1630-6827)
- Aicha Jeridi (ORCID: https://orcid.org/0000-0002-2120-936X)
- Michal Mastalerz
- Elisabeth Hennen
- Sai Rama Sridatta Prakki
- Bart M. Vanaudenaerde (ORCID: https://orcid.org/0000-0001-6435-6901)
- Mircea-Gabriel Stoleriu
- Hannah Marchi (ORCID: https://orcid.org/0000-0003-0607-6033)
- Benedikt Jäger
- Markus Klotz
- Claudia A Staab-Weijnitz
- Marie Zöller
- Herbert Schiller
- Ronan LeGleut
- Antje Prasse
- Laurens J. De Sadeleer
- Wim A. Wuyts
- Ali Ö. Yildirim
Institutions
- Helmholtz Zentrum München (DE)
- Fraunhofer Institute for Toxicology and Experimental Medicine (DE)
- German Center for Lung Research (DE)
- Centre de Recherche en Cancérologie de Marseille (FR)
- University of Colorado Anschutz Medical Campus (US)
- Ludwig-Maximilians-Universität München (DE)
- KU Leuven (BE)
Publication Details
- Journal
- Scientific Reports
- Published
- 2026-05-11
- DOI
- https://doi.org/10.1038/s41598-026-51510-1
- Primary Topic
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- University of Colorado
- Deutsche Forschungsgemeinschaft
- Helmholtz Association
- Deutsches Zentrum für Lungenforschung
- European Research Council