Healthy lung tissue depends on a delicate balance between producing structural support proteins — collectively known as the extracellular matrix (ECM) — and breaking them down when necessary. In pulmonary fibrosis, this balance is disrupted. Too much collagen and elastin accumulate, thickening the lung tissue and reducing its elasticity.
The breakdown of these structural proteins is largely carried out by enzymes called matrix metalloproteinases (MMPs). These enzymes are produced by key lung cells, including fibroblasts and macrophages. If MMP levels fall, collagen and elastin can build up excessively.
The new study demonstrates that TRPML1 plays a crucial role in regulating the release of several MMPs from lung cells. Specifically, loss of TRPML1 reduced extracellular levels of MMP2, MMP8, MMP9, MMP12 and MMP19 — all enzymes involved in degrading collagen and elastin.
Researchers used genetically modified mice lacking the TRPML1 gene. These mice showed clear signs of lung dysfunction. Measurements of lung mechanics revealed increased stiffness and reduced compliance — hallmark features of fibrosis. Tissue analysis confirmed excessive deposition of collagen and elastin, resembling the effects of bleomycin, a drug commonly used to experimentally induce fibrosis.
Importantly, the reduced MMP levels were not due to decreased gene expression. Instead, the problem lay in impaired lysosomal exocytosis — a cellular process by which enzymes stored inside vesicles are released outside the cell. TRPML1 is a channel located in lysosomes (cellular compartments involved in recycling and secretion). When TRPML1 was absent, lysosomal release of MMPs was disrupted, limiting their availability in the extracellular space.
Mutations in TRPML1 are known to cause a rare genetic disorder called mucolipidosis type IV (MLIV), primarily characterised by neurological and developmental problems. This study suggests that individuals with MLIV may also be at risk of developing lung fibrosis later in life.
Encouragingly, the researchers also showed that activating TRPML1 with small molecules increased MMP release, raising the possibility that targeting this pathway could offer a new therapeutic strategy for fibrotic lung disease.
Rather than focusing solely on blocking inflammation — an approach that has had limited success — this research highlights the importance of restoring the lung’s ability to remodel its extracellular matrix. By identifying TRPML1 as a regulator of enzyme release that prevents excessive scarring, the study opens up a promising new avenue for antifibrotic therapies.
In short, TRPML1 appears to function as a molecular “brake” on lung fibrosis. When it fails, scar tissue builds up. When it works, the lungs maintain their flexibility — and their ability to sustain life.
Full paper: https://link.springer.com/article/10.1038/s44318-026-00712-4