ADAM17 (ADAM metallopeptidase domain 17) is a transmembrane metalloprotease that serves as a critical molecular switch in cellular signaling through ectodomain shedding of membrane-bound proteins 1. The enzyme cleaves numerous substrates including cytokines (TNF-α), growth factors (EGF), adhesion proteins (L-selectin), and their receptors (IL-6R), playing essential roles in inflammation, immunity, and cell signaling 1. ADAM17 requires obligate binding partners iRhom1/2 for proper maturation and activation, with structural studies revealing how these interactions regulate enzymatic function 2. The protease activates Notch signaling pathways and processes substrates like PLA2R1 through both constitutive and stimulated mechanisms involving ADAM10 3. Disease relevance includes roles in cancer progression, where ADAM17 confers temozolomide resistance in glioblastoma and is regulated by miR-145 4. ADAM17 variants cause hypotrichosis through TRIM47-mediated protein degradation, affecting hair follicle stem cell function via impaired Notch signaling 5. The enzyme promotes vascular inflammation and atherosclerosis development 6, and contributes to various fibrotic diseases across multiple organs 7. Clinically, dysregulated ADAM17 activity is implicated in inflammatory skin and bowel disease, making it an attractive therapeutic target 8.