Am J Respir Crit Care Med. 2026 Jul 28:aamag396. doi: 10.1093/ajrccm/aamag396. Online ahead of print.

ABSTRACT

RATIONALE: Yes-associated protein (YAP)-mediated fibroblast mechanoactivation is an important driver of fibrosis in idiopathic pulmonary fibrosis (IPF).

OBJECTIVE: To characterize the role of ADAM with Thrombospondin motifs 14 (ADAMTS14) in YAP-mediated fibroblast mechanoactivation and pulmonary fibrosis.

METHODS: We disrupted ADAMTS14 expression in primary human lung fibroblasts (HLFs) and demonstrated its role in YAP nuclear translocation and fibroblast activation. We confirmed the in vivo relevance of ADAMTS14 in an IPF patient cohort using transcriptomic studies. ADAMTS14-deficient fibroblasts were further characterized in mechanistic studies combining advanced microscopy, unbiased proteomics, and co-immunoprecipitation with functional mechanobiology assays to delineate substrate-matrix interactions.

RESULTS: An unbiased siRNA screen identified ADAMTS14 as a regulator of YAP-mediated fibroblast activation and pro-fibrotic activity. Transcriptomic analyses of patient samples with fibrotic lung disease identified an ADAMTS14-expressing fibroblast population characterized by excessive collagen matrix synthesis and located within fibroblastic foci of IPF patients. Disruption of ADAMTS14 expression in IPF patient-derived HLFs reduced pro-fibrotic gene expression and attenuated the response to TGFβ. Mechanistically, we identified collagen V as a novel functionally relevant ADAMTS14 substrate essential for matrix stability. ADAMTS14-deficient fibroblasts produced an unstable extracellular matrix, leading to disorganized focal adhesions, impaired force transmission, and reduced focal adhesion-FAK-AKT signaling.

CONCLUSION: We identify a novel ADAMTS14-collagen V-focal adhesion axis as a potential driver of fibroblast activation in IPF, linking extracellular proteolytic matrix remodeling to focal adhesion dynamics and YAP-mediated mechanoactivation. This feed-forward circuit provides a new mechanistic framework for pulmonary fibrosis and identifies potential novel therapeutic targets.

PMID:42518202 | DOI:10.1093/ajrccm/aamag396