TIMP2 is a metalloproteinase inhibitor that functions through both canonical and non-canonical mechanisms in tissue homeostasis and disease. Classically, TIMP2 inactivates matrix metalloproteinases (MMPs) including MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, and MMP-9 by binding to their catalytic zinc cofactor 1. Beyond MMP inhibition, TIMP2 exhibits cytokine-like activity through receptor binding. In traumatic brain injury, TIMP2 protects blood-brain barrier integrity via α3β1 integrin-mediated inhibition of Src-dependent VE-cadherin internalization, independently of MMP inhibition 1. In diabetic nephropathy, TIMP2 expression is modulated by METTL3-mediated m6A methylation and promotes podocyte injury through Notch signaling activation 2. During ischemia-reperfusion injury, TIMP2 upregulation in renal tubular epithelial cells promotes fibrogenesis via syndecan-4-dependent Hedgehog signaling, driving mitochondrial fragmentation and glycolytic reprogramming 3. TIMP2 expression is epigenetically regulated by hypoxia-inducible factor 1-alpha binding to its promoter under hypoxic conditions 4. In colorectal cancer, TIMP2 expression is suppressed through DNMT3A-mediated DNA methylation, and restoring TIMP2 inhibits cancer cell migration and invasion 5. TIMP2 genetic polymorphisms show associations with primary open-angle glaucoma 6 but not with urological cancer risk 7. These findings identify TIMP2 as a multifunctional mediator of tissue remodeling with distinct roles depending on pathological context.