Macrophage Migration Inhibitory Factor: Its Multifaceted Role in Inflammation and Immune Regulation Across Organ Systems.

Macrophage Migration Inhibitory Factor (MIF) is a pleiotropic cytokine that acts as a central regulator of inflammation and immune responses across diverse organ systems. Functioning upstream in immune activation cascades, MIF influences macrophage polarization, T and B cell differentiation, and cytokine expression through CD74, CXCR2/4/7, and downstream signaling via NF-κB, ERK1/2, and PI3K/AKT pathways. This review provides a comprehensive analysis of MIF's mechanistic functions under both physiological and pathological conditions, highlighting its dual role as a protective mediator during acute stress and as a pro-inflammatory amplifier in chronic disease. MIF's involvement in autoimmune disorders, neurodegeneration, metabolic syndromes, infectious diseases, and oncogenesis is examined, with particular attention to its contribution to immune dysregulation, immune escape, and the shaping of inflammatory microenvironments. Its clinical relevance as a biomarker is underscored by associations between elevated serum levels, polymorphic variants such as the -173 G>C SNP, and disease susceptibility, progression, and therapeutic response. Advances in therapeutic strategies are also discussed, including the development of small-molecule inhibitors, MIF-2-specific antagonists, CD74-targeted therapies, and gene-based interventions. Taken together, emerging evidence positions MIF as both a diagnostic indicator and a therapeutic target, with its broad regulatory functions across immune, vascular, and metabolic pathways emphasizing its relevance in precision immunotherapy and its potential to serve as a strategic axis in the future of translational medicine.