The Evolution, Oligomerization, Function, and Action Mechanism of α2-Macroglobulin.

α2-Macroglobulin (A2M), a large tetrameric glycoprotein with a molecular weight of approximately 720 kDa, is a key member of the α-macroglobulin superfamily. Its origin dates back 600-700 million years, positioning A2M as an evolutionary link within the α-macroglobulin family and complement components C3, C4, and C5. Structural predictions of A2M across different species reveal a remarkably high degree of conservation between invertebrates and vertebrates. A2M is abundantly present in the body fluids of both vertebrates and invertebrates, and its diverse biological functions are governed by five key functional domains within its molecular structure. The most well-established role of A2M is the entrapment and inhibition of proteases. Beyond that, it interacts with cytokines, growth factors, and membrane receptors, thereby playing a broad role in immune and inflammatory responses, hemostasis and coagulation, as well as in disease mechanisms and therapeutic processes. This review summarizes the origin and evolution of A2M, its molecular structure and functional domains, principal mechanisms of action, and research progress regarding its functions in both invertebrates and vertebrates. Our goal is to provide new insights and directions for further exploring the functional potential of A2M and its future applications in the treatment of clinical diseases.