LACTYLATION related genes may offer new therapeutic targets for idiopathic pulmonary fibrosis, according to multiomics research.
Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial lung disease associated with high mortality. Although lactylation, a recently identified posttranslational modification, has been linked to inflammation and tissue fibrosis, its contribution to IPF remains incompletely understood.
Researchers have now identified three lactylation related hub genes that may contribute to disease progression through epithelial changes, fibroblast activation, and remodeling of the immune environment.
New Therapeutic Targets in IPF Identified
The researchers analyzed transcriptomic and single cell sequencing data from lung tissue collected from patients with IPF and healthy controls. Gene coexpression analysis, protein interaction networks, and cellular clustering were used to identify genes associated with both lactylation and IPF.
The analysis identified DDX3X, BCLAF1, and NCL as central lactylation related genes. Their expression varied across lung cell populations. DDX3X was primarily detected in macrophages and neutrophils, BCLAF1 in ciliated epithelial cells, and NCL in lung fibroblasts and macrophages.
All three genes were significantly upregulated in IPF tissue compared with healthy lung tissue. Overall lactylation levels were also significantly elevated in IPF lungs and in cellular models stimulated with transforming growth factor beta 1.
Gene Knockdown Limits Fibrotic Activity
Functional experiments provided preliminary evidence that the three genes may actively contribute to fibrosis. Individually suppressing DDX3X, BCLAF1, or NCL significantly inhibited alveolar epithelial to mesenchymal transition and reduced activation of human fetal lung fibroblasts.
These processes are central to fibrotic remodeling. Epithelial to mesenchymal transition can promote the development of cells with profibrotic properties, while activated fibroblasts contribute to excessive extracellular matrix accumulation and progressive lung scarring.
The genes were also closely associated with altered immune cell infiltration, suggesting that aberrant lactylation may support a profibrotic immune microenvironment in idiopathic pulmonary fibrosis.
Findings Support Further Therapeutic Research
Molecular docking analyses showed favorable predicted binding between proteins encoded by the three hub genes and pirfenidone and curcumin. However, these computational findings do not establish clinical effectiveness and require further experimental validation.
The results position DDX3X, BCLAF1, and NCL as potential therapeutic targets in IPF while highlighting lactylation as a possible mechanism underlying disease progression. Further studies are needed to determine whether targeting these genes or lactylation pathways can produce clinically meaningful antifibrotic effects.
Reference
Yue M et al. Identification and functional validation of lactylation-related hub genes in idiopathic pulmonary fibrosis based on multi-omics analysis. Respir Res. 2026;DOI:10.1186/s12931-026-03783-3.
Featured Image: Viacheslav Yakobchuk on Adobe Stock.
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