β2-microglobulin as a multifaceted biomarker and regulatory molecule in multisystem diseases: A comprehensive review

β2-microglobulin (B₂M), a structural component of major histocompatibility complex class I (MHC-I), is widely expressed on the surface of all nucleated cells, and exists in free form in blood, urine, and cerebrospinal fluid. Under normal physiological conditions, B₂M associates noncovalently with the MHC-I heavy chain, thereby supporting proper folding, peptide loading, complex stability, and cell surface expression; the assembled peptide-MHC-I complex is then recognized by CD8⁺ cytotoxic T cells during immune surveillance. B₂M is primarily eliminated through glomerular filtration, proximal tubular reabsorption, and metabolic clearance. In recent years, B₂M metabolic and expression abnormalities have been observed in various diseases, where it contributes to pathological processes such as inflammatory signaling, regulation of apoptosis, iron metabolism, and tumor immune evasion. B₂M has demonstrated potential value as a biomarker in multisystem diseases. This comprehensive review synthesizes current evidence on B₂M's multifaceted roles as a biomarker and functional regulator across cardiovascular, respiratory, renal and urinary, central nervous system, immune, neoplastic, and locomotor system disorders. We focus on the molecular mechanisms underlying these abnormalities and evaluate the evidence supporting B₂M as a candidate biomarker for diagnosis, assessment of disease activity or progression, and prognosis across different diseases. This review underscores B₂M's emerging significance beyond renal function, linking it to multisystem disease pathogenesis and translational medicine.