ADAMTS4 is a zinc-dependent metallopeptidase that primarily functions in extracellular matrix degradation, particularly of cartilage proteoglycans. The enzyme cleaves aggrecan at specific sites and also degrades COMP (cartilage oligomeric matrix protein), playing a critical role in cartilage turnover 1. ADAMTS4 operates through its metalloproteinase domain and thrombospondin motifs to process ECM components in the extracellular space 2. The enzyme's expression is regulated by proinflammatory cytokines and the NF-κB transcription factor, with IL-6 inducing increased production via PI3K/Akt signaling pathways 34. ADAMTS4 has significant disease relevance in osteoarthritis, where excessive aggrecanase activity contributes to cartilage degradation and joint destruction 52. Beyond joint disease, ADAMTS4 also participates in acute respiratory distress syndrome, where damage-responsive fibroblasts produce the enzyme to remodel lung ECM, promoting immune cell infiltration but compromising lung function 6. Clinically, ADAMTS4 levels in respiratory tract correlate with infection severity, and the enzyme represents a potential therapeutic target for both osteoarthritis and ARDS, with neutralizing antibodies showing promise in preclinical studies 16.