The Digester

p38 MAPK links epigenetic changes to pro-fibrotic gene activation in senescent lung fibroblasts

Mar 9th 2026

A new study using human lung fibroblasts shows that p38 MAPK activity drives TGF-β1-induced upregulation of key fibrotic genes by increasing promoter H4K16 acetylation, with near-senescent cells displaying a slower but sustained p38 response and p38 inhibition lowering pro-fibrotic gene expression in cell models and primary IPF fibroblasts.

  • TGF-β1 increases α-SMA and Col3A1 expression in both young (LPDL) and near-senescent/senescent (HPDL) IMR90 human lung fibroblasts.
  • HPDL fibroblasts show a delayed but sustained p38 MAPK phosphorylation response to TGF-β1 compared with an earlier peak in LPDL cells.
  • Pharmacologic inhibition of p38 MAPK (SB202190) reduces α-SMA and Col3A1 mRNA and protein in TGF-β1-treated IMR90 cells and in primary IPF fibroblasts.
  • TGF-β1 raises global H4K16 acetylation and increases H4K16ac enrichment at α-SMA and Col3A1 promoters, and p38 MAPK inhibition attenuates both effects.
  • The results support a p38 MAPK-dependent epigenetic mechanism for fibroblast activation and reinforce p38 MAPK as a candidate target for age-related lung fibrosis therapies.

Sources

doi.org