Alpha-2-macroglobulin (A2M) is a broad-spectrum serine protease inhibitor that functions through a unique 'trapping' mechanism, wherein proteinase cleavage of its bait region induces conformational changes that entrap the enzyme while allowing activity against small substrates 1. Beyond protease inhibition, A2M functions as a multi-functional regulator of inflammatory and oxidative stress pathways with emerging clinical significance. Mechanistically, A2M inhibits inflammatory mediators by neutralizing IL-1β and blocking downstream NF-κB signaling in chondrocytes, thereby reducing matrix metalloproteinase expression and protecting cartilage 1. In pathological contexts, A2M activates the Keap1/Nrf2 antioxidant pathway and promotes anti-inflammatory macrophage differentiation, mitigating glucocorticoid-induced osteonecrosis 2. A2M also regulates vascular smooth muscle cell phenotype switching via the RhoA-GTPase pathway, with A2M-LRP1 signaling implicated in preeclampsia pathogenesis 3. Clinically, A2M dysfunction associates with multiple diseases including neurodegeneration (Alzheimer's disease through zinc dyshomeostasis) 4, lung cancer (progressive A2M loss correlates with paclitaxel resistance development) 5, and infantile pulmonary inflammatory myofibroblastic tumors carrying A2M-ALK fusion genes 6. Intra-articular A2M injection shows modest, comparable efficacy to PRP and corticosteroids for knee osteoarthritis 7, though cost-effectiveness remains questionable for routine clinical application.