The ADAMTS family: from extracellular matrix proteases to orchestrators of fibrosis

Fibrosis, a pathological process defined by excessive extracellular matrix (ECM) accumulation, contributes significantly to chronic organ failure worldwide. The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family proteins are secreted, multi-domain matrix-associated zinc metalloendopeptidases, which have emerged as key regulators of fibrotic pathogenesis. While the ADAMTS proteins are well known for their ability to cleave ECM components such as collagens, proteoglycans, fibronectin, and fibrillins, their roles in fibrosis extend beyond conventional ECM modulators. Through precise proteolytic modification of these ECM substrates, ADAMTS members actively orchestrate upstream and core mechanisms driving fibrosis, notably TGF-β activation and fibroblast phenotype switching. Recent studies have uncovered tissue- and substrate-specific roles of individual ADAMTS members, highlighting their dual regulatory effects in fibrotic diseases and opening avenues for targeted therapeutic strategies. Despite promising preclinical results, translating ADAMTS-targeting therapies into clinical applications for fibrosis remains challenging due to their functional duality, substrate redundancy, and poorly characterized spatiotemporal specificity. This review comprehensively summarizes the proteolytic mechanisms of ADAMTS proteases toward ECM substrates, their multifaceted roles in fibrogenesis, and discusses their translational potential as therapeutic targets.