Abstract

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that occupies a central regulatory position within pulmonary immune networks, integrating inflammatory signalling, redox control, and immune–stromal communication. Originally characterized as a proinflammatory mediator, MIF is now recognized to exert context-dependent functions that range from protective host defense during acute infection to pathogenic promotion of chronic inflammation, fibrosis, and tumor progression when regulatory constraints fail. This review synthesises current evidence on the molecular biology, structural features, and signalling mechanisms that govern MIF activity in the lung, emphasising its role as a network hub coordinating CD74/CD44- and CXCR-mediated signalling, glucocorticoid antagonism, and redox imbalance. A systems biology perspective is used to illustrate how genetic variability, environmental exposures, ageing, and metabolic stress reprogram MIF-centred immune circuits across pulmonary disease states. Integration of multi-omics insights, systems pharmacology, and computational modeling highlights emerging opportunities for precision modulation of MIF signaling rather than indiscriminate inhibition. Disease-specific manifestations of MIF dysregulation in pneumonia, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and lung cancer are discussed as dynamic outcomes of shared regulatory architectures. Collectively, this review positions MIF as a critical immunoregulatory node whose context-dependent modulation offers promising avenues for biomarker development and targeted therapeutic intervention in complex pulmonary disorders.