MATN3 (matrilin-3) is a cartilage extracellular matrix component that functions as a major structural constituent involved in the formation of extracellular filamentous networks 1. Beyond its classical skeletal role, MATN3 has emerged as a pleiotropic protein with neuroprotective functions. In ischemic stroke, matrilin-3 suppresses astrocyte-mediated neuroinflammation by entering astrocytes via caveolin-1-mediated endocytosis, translocating to the nucleus where it binds NF-κB p65 to suppress inflammatory cytokine transcription, while also blocking the BMP-2/Smads pathway 2. GenetSTIC relevance includes skeletal dysplasias, where MATN3 variants are associated with short stature and multiple epiphyseal dysplasia 1. Regarding osteoarthritis, the T303M polymorphism may associate with trapeziometacarpal rather than digital osteoarthritis 3, though a specific SNP (rs77245812) showed no association with knee osteoarthritis in Mexican mestizos 4. Clinically significant findings include MATN3's aberrant methylation and upregulation in gastric adenocarcinoma, where high expression independently predicts poor prognosis 56. In stomach adenocarcinoma, MATN3 promotes cell proliferation and migration while modulating amino acid metabolism 7. MATN3 also functions as a tumor suppressor in triple-negative breast cancer through extracellular matrix organization regulated by HOXB2 8.