ORCID
0000-0001-6575-9729 (Sanders)
Document Type
Article
Publication Date
2026
DOI
10.18632/aging.206357
Publication Title
Aging
Volume
18
Issue
1
Pages
67-81
Abstract
Fibroblast activation is essential for tissue repair following injury; however, prolonged activation drives pathological fibrosis. Idiopathic pulmonary fibrosis (IPF), a progressive and age-associated lung disease, is characterized by aberrant fibroblast activation, with increasing evidence implicating senescent and near-senescent fibroblasts in its pathogenesis. However, the underlying mechanisms remain poorly defined. In this study, we investigated whether histone modification is involved in TGF-β1 treated lung fibroblasts and contributes to the fibrotic phenotype. Human IMR90 lung fibroblasts at low and high population doubling levels (LPDL and HPDL), as well as primary IPF fibroblasts, were used in this study. In response to TGF-β1, both LPDL and HPDL fibroblasts upregulated profibrotic genes, including α-smooth muscle actin (α-SMA) and Collagen type III alpha 1 (Col3A1). Compared with LPDL fibroblasts, HPDL fibroblasts exhibited a delayed and sustained p38 MAPK response. Pharmacological inhibition of p38 MAPK significantly reduced α-SMA and Col3A1 expression in both TGF-β1-stimulated fibroblasts and primary IPF cells. Mechanistically, TGF-β1-induced expression of α-SMA and Col3A1 was mediated by histone H4K16 acetylation (H4K16ac), which was enriched at gene promoter regions and attenuated by p38 MAPK inhibition. These findings suggest that a p38 MAPK–dependent epigenetic mechanism is involved in fibroblast activation, supporting the therapeutic potential of p38 MAPK inhibition for treating age-related fibrotic diseases such as IPF.
Rights
Copyright: © 2026 Zhu et al.
This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Original Publication Citation
Zhu, S., Zhou, J. Q., Wang, K., Guo, M. L., & Sanders, Y. Y. (2026). P38 MAPK is involved in epigenetic regulation of fibrotic genes in replication induced senescence in lung fibroblasts. Aging, 18(1), 67-81. https://doi.org/10.18632/aging.206357
Repository Citation
Zhu, S., Zhou, J. Q., Wang, K., Guo, M. L., & Sanders, Y. Y. (2026). P38 MAPK is involved in epigenetic regulation of fibrotic genes in replication induced senescence in lung fibroblasts. Aging, 18(1), 67-81. https://doi.org/10.18632/aging.206357
Supplementary Table
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