Loss of PKN2 drives fibroblast reprogramming and extracellular matrix remodelling in pulmonary fibrosis
- 1University of Leicseter
Abstract
Introduction Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease characterised by aberrant fibroblast function, extracellular matrix (ECM) remodelling and defective tissue repair. Protein kinase N2 (PKN2) is associated with accelerated forced vital capacity decline in IPF, but its functional role in pulmonary fibrosis remains unknown. We hypothesised that PKN2 regulates fibroblast phenotype and tissue repair. Methods PKN2 expression was assessed in human lung tissue, induced sputum and primary airway and parenchymal fibroblasts from non-fibrotic controls and patients with interstitial lung disease (ILD). DNA methylation was profiled using the Illumina HumanMethylationEPIC array. PKN2 function was investigated by siRNA-mediated depletion in primary human lung fibroblasts using transcriptomic, proteomic and functional analyses. Tissue repair was assessed following pharmacological PKN inhibition in zebrafish. Results PKN2 expression was reduced in ILD lung tissue and primary airway and parenchymal fibroblasts and further suppressed by TGF-{beta}1. Differential methylation was identified across the PKN2 locus in both fibroblast populations. Integrated transcriptomic and proteomic profiling following PKN2 depletion revealed coordinated remodelling of ECM, cell adhesion, non-canonical WNT and VEGF pathways, including dysregulation of COL1A1, WNT, VEGF and MMP1. PKN2 loss increased VEGF and MMP-1 secretion and accelerated fibroblast wound closure. PKN inhibition altered epithelial organisation and collagen fibre alignment during zebrafish wound repair. Conclusion PKN2 loss drives fibroblast reprogramming and aberrant ECM remodelling, establishing PKN2 as an important regulator of pulmonary fibroblast homeostasis and tissue repair.
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BibTeX
@misc{mcmullan2026loss,
title = {{Loss of PKN2 drives fibroblast reprogramming and extracellular matrix remodelling in pulmonary fibrosis}},
author = {C. E. McMullan and O. A. Pena and P. Rajasekar and A. Valand and P. Stylianou and G. Elliott and M. Whitfield and M. Ratnasingham and S. Narayan and A. J. Hall and B. Goncalves and V. Mistry and L. Carr and H. Marshall and B. Liu and D. J. L. Jones and P. Bradding and R. J. Allen and L. V. Wain and R. L. Clifford and C. B. Maxwell and K. M. Roach},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.02.748906},
url = {https://www.biorxiv.org/content/10.64898/2026.09.02.748906v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Loss of PKN2 drives fibroblast reprogramming and extracellular matrix remodelling in pulmonary fibrosis
AU - C. E. McMullan
AU - O. A. Pena
AU - P. Rajasekar
AU - A. Valand
AU - P. Stylianou
AU - G. Elliott
AU - M. Whitfield
AU - M. Ratnasingham
AU - S. Narayan
AU - A. J. Hall
AU - B. Goncalves
AU - V. Mistry
AU - L. Carr
AU - H. Marshall
AU - B. Liu
AU - D. J. L. Jones
AU - P. Bradding
AU - R. J. Allen
AU - L. V. Wain
AU - R. L. Clifford
AU - C. B. Maxwell
AU - K. M. Roach
PY - 2026
DA - 2026/09/02
PB - bioRxiv
DO - 10.64898/2026.09.02.748906
UR - https://www.biorxiv.org/content/10.64898/2026.09.02.748906v1
AB - Introduction Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease characterised by aberrant fibroblast function, extracellular matrix (ECM) remodelling and defective tissue repair. Protein kinase N2 (PKN2) is associated with accelerated forced vital capacity decline in IPF, but its functional role in pulmonary fibrosis remains unknown. We hypothesised that PKN2 regulates fibroblast phenotype and tissue repair. Methods PKN2 expression was assessed in human lung tissue, induced sputum and primary airway and parenchymal fibroblasts from non-fibrotic controls and patients with interstitial lung disease (ILD). DNA methylation was profiled using the Illumina HumanMethylationEPIC array. PKN2 function was investigated by siRNA-mediated depletion in primary human lung fibroblasts using transcriptomic, proteomic and functional analyses. Tissue repair was assessed following pharmacological PKN inhibition in zebrafish. Results PKN2 expression was reduced in ILD lung tissue and primary airway and parenchymal fibroblasts and further suppressed by TGF-{beta}1. Differential methylation was identified across the PKN2 locus in both fibroblast populations. Integrated transcriptomic and proteomic profiling following PKN2 depletion revealed coordinated remodelling of ECM, cell adhesion, non-canonical WNT and VEGF pathways, including dysregulation of COL1A1, WNT, VEGF and MMP1. PKN2 loss increased VEGF and MMP-1 secretion and accelerated fibroblast wound closure. PKN inhibition altered epithelial organisation and collagen fibre alignment during zebrafish wound repair. Conclusion PKN2 loss drives fibroblast reprogramming and aberrant ECM remodelling, establishing PKN2 as an important regulator of pulmonary fibroblast homeostasis and tissue repair.
ER -