Scars are supposed to be permanent. That assumption has shaped how we think about idiopathic pulmonary fibrosis (IPF), a disease in which the lung replaces its delicate gas-exchanging tissue with stiff scar, until breathing fails. Median survival after diagnosis is often reported as approximately three to five years. A study led by the group of Elie El Agha at the Cardio-Pulmonary Institute, now published in Nature Communications, challenges that assumption and pinpoints a fibroblast population that decides whether the lung heals or stays broken.

Using genetic lineage tracing to track individual fibroblasts through fibrosis and recovery in aged mice, the team uncovered a reversible switch. As fibrosis develops, lipid-storing lipofibroblasts convert into scar-forming myofibroblasts. During healthy resolution, this conversion runs backwards, myofibroblasts revert to their benign state and the lung repairs. Fibrosis, in other words, is reversible by design.

But aged lungs don't complete the reversal. A distinct population of alveolar fibroblasts marked by the matrix-remodelling enzyme ADAMTS4 refuses to stand down, persisting long after injury has passed and holding the lung in a fibrotic state.

"The lung has a built-in capacity to reverse scarring; aging breaks that reversibility," say co-first authors Mahsa Zabihi and Ali Khadim. "A persistent ADAMTS4-positive population keeps the lung locked in disease. It reframes IPF as a failure of resolution, not simply an excess of scarring."

The findings hold in human disease: mining transplant tissue and single-cell and spatial datasets, the team found ADAMTS4-positive fibroblasts concentrated within the fibrotic regions of IPF lungs. The axis also proved targetable: in precision-cut human lung slices and alveolar organoids, modulation of the ADAMTS4–versican–TIMP-3 axis, including ADAMTS4 silencing, attenuated fibrogenesis.

"By identifying ADAMTS4 as both a marker and a driver of impaired resolution, we move from describing fibrosis to having a handle on reversing it," notes Elie El Agha. The message inverts decades of thinking: pulmonary fibrosis may not be a permanent scar, but a stalled repair , held open by a specific, targetable population of cells.

Find the full article here: https://www.nature.com/articles/s41467-026-72419-3