ADAMTS8 is a secreted zinc-dependent metalloproteinase with anti-angiogenic properties that functions primarily as a tumor suppressor across multiple cancer types. Mechanistically, ADAMTS8 cleaves osteopontin and regulates extracellular matrix organization through proteolytic activity 1, with post-translational regulation involving autolysis and inhibition by TIMP-2 and TIMP-3 1. The protease operates through multiple signaling pathways: it suppresses VEGFA-mediated angiogenesis in lung cancer 2, inhibits the EGFR/Akt signaling pathway in breast cancer 3, and participates in PPARG/ADAMTS8 signaling regulating extracellular matrix genes in osteoarthritis 4. Disease relevance is substantial: low ADAMTS8 expression predicts poor prognosis in breast cancer, with high ADAMTS8 and low ADAMTS15 conferring >5-fold increased mortality risk 5. ADAMTS8 overexpression inhibits cell proliferation, migration, and invasion while inducing G2/M arrest in breast cancer 3 and suppresses glioma development in vitro and in vivo 6. Clinically, ADAMTS8 serves as an independent prognostic biomarker for breast cancer overall survival 3, with genetic variants at the ADAMTS8 locus associated with hypothalamic volume and neuropsychiatric traits 7, suggesting broader neurobiological significance beyond cancer.