Idiopathic pulmonary fibrosis (IPF) is one of the most severe chronic lung diseases. It leads to progressive scarring of lung tissue and increasingly impairs breathing. Although the mechanisms driving fibrosis formation have been intensively studied, little is known about why lung tissue fails to recover in some cases.
A research team involving scientists from the German Center for Lung Research (DZL) has now gained important insights into the processes that determine whether pulmonary fibrosis progresses or resolves. The findings were published in Nature Communications.
Using advanced lineage tracing, single-cell analyses, and experimental models, the researchers investigated how specific connective tissue cells in the lung change during the development and resolution of fibrosis. They found that so-called lipofibroblasts transform into myofibroblasts during disease progression — the cells primarily responsible for scar formation.
Remarkably, the study showed that this process is reversible: during tissue repair, myofibroblasts can revert back into lipofibroblasts. This reversible cell-state transition appears to be a key prerequisite for fibrosis resolution.
However, in models of delayed fibrosis resolution, the researchers identified a population of cells that persisted over time. These cells were characterized by the production of the protein ADAMTS4.
The analyses demonstrated that the persistence of these ADAMTS4-positive cells is closely associated with failed tissue repair. Additional investigations using human lung tissue as well as spatial and single-cell transcriptomic data confirmed the clinical relevance of the findings.
The results suggest that ADAMTS4 plays an important role in maintaining fibrotic processes. Targeting this pathway could therefore open new possibilities for promoting fibrosis resolution and slowing disease progression.
“Our study shows that fibrosis resolution is not a passive process, but is actively regulated through fibroblast plasticity,” the authors explain. Identifying ADAMTS4 as a key factor opens new perspectives for the development of future therapies against pulmonary fibrosis.
Original publication
Zabihi M., Khadim A., Lingampally A. et al. Persistence of alveolar fibroblast-derived ADAMTS4+ cells in a preclinical model of delayed pulmonary fibrosis resolution. Nature Communications (2026). DOI: 10.1038/s41467-026-72419-3 .
