ADAMTS14 is a novel modulator of fibroblast mechanoactivation in pulmonary fibrosis

Abstract Rationale Yes-associated protein (YAP)–mediated fibroblast mechanoactivation is an important driver of fibrosis in idiopathic pulmonary fibrosis (IPF). Objectives To characterize the role of ADAM with thrombospondin motif 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. Measurements and Main Results An unbiased siRNA screen identified ADAMTS14 as a regulator of YAP-mediated fibroblast activation and profibrotic 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 profibrotic 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. Conclusions 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.