Human α2‐Macroglobulin: Architecture, Mechanisms, and Functional Implications

α2-Macroglobulin (α2M) is a large glycoprotein and one of the most abundant proteins found in the plasma of vertebrates and in the hemolymph of invertebrates. It performs several important functions in the innate immune system, serving as a pan-protease inhibitor and contributing to essential processes, such as cytokine and hormone transport. It also triggers diverse cellular responses, critical for the functioning of both eukaryotic and some prokaryotic biological systems. Here, we focus on the human α2-macroglobulin (hα2M) molecule, compiling relevant information from recent studies on its structure and how this relates to its unique protease capture mechanism. In addition, we summarize other findings accumulated over 50 years of literature on hα2M. We also discuss its distinctive electrophoretic behavior, its dimeric form, and its potential role in inflammatory environments, as well as the basic unit of hα2M for protease capture. We summarize some challenges encountered in hα2M structural studies, a distinctive mechanism of incorporation of non-proteolytic ligands, and remarks and details on its purification and storage. Although the clinical use of hα2M is currently limited mainly to its role as a secondary biomarker for certain disorders, new therapeutic approaches have begun to emerge in initial studies over the past decade. The study of hα2M remains highly relevant for understanding unknown aspects of the innate immune system, developing new therapies, elucidating infection and inflammation processes, exploring potential links to mechanisms of cancer resistance, and advancing other fields critically important to translational and clinical research.