{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMacrophage migration inhibitory factor (MIF) is an evolutionarily conserved, pleiotropic cytokine that plays a central role in the regulation of innate and adaptive immunity. It acts as an early upstream activator of monocytes/macrophages, counter-regulates the anti‐inflammatory effects of glucocorticoids, and modulates production of other inflammatory mediators. Genetic studies have linked functional polymorphisms in the MIF gene with disease severity in conditions such as rheumatoid arthritis, systemic‐onset juvenile idiopathic arthritis, and other inflammatory disorders, thereby underscoring its importance in controlling the overall inflammatory tone."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMIF exerts many of its biological functions by interacting with specific cell surface receptors. It binds to CD74 and forms receptor complexes with chemokine receptors—most notably CXCR2, CXCR4, and CXCR7—which in turn activate downstream signaling cascades such as the mitogen‐activated protein kinase (MAPK) pathways (including ERK1/2 and JNK), PI3K/AKT, and p38. These receptor‐mediated interactions are critical for mediating rapid leukocyte arrest, chemotaxis, integrin activation, and cell adhesion, thus orchestrating the inflammatory cell recruitment observed in a range of conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its receptor‐mediated actions, MIF is released via non‐classical secretory pathways that bypass the endoplasmic reticulum, involving transporters like ABCA1 and chaperones such as p115. Once released, MIF plays a multifaceted role in cellular stress responses, including cardioprotection by promoting AMP‐activated protein kinase (AMPK) activation during ischemia–reperfusion injury and in modulating oxidative stress. Moreover, MIF can function intracellularly as a nuclease in a poly(ADP‐ribose) polymerase‐1 (PARP‐1)–dependent cell death pathway and can modify apoptotic signaling—partly through its redox activity that impacts c‐Jun N-terminal kinase (JNK) activation—thereby influencing cell survival under stress."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical roles in inflammation and stress response, MIF has emerged as a critical mediator in the pathogenesis of various human diseases, including numerous cancers and metabolic disorders. It promotes tumorigenesis by enhancing cell proliferation, epithelial-to-mesenchymal transition, angiogenesis, and invasion, while also modulating the tumor microenvironment through the recruitment of myeloid-derived suppressor cells and by altering cytokine networks. MIF’s actions have been implicated in the aggressiveness of prostate, pancreatic, breast, ovarian, and nasopharyngeal cancers, as well as in pathological tissue remodeling processes seen in diabetic nephropathy. These multifaceted roles highlight MIF as a potential target for therapeutic intervention in cancer and other MIF-driven diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "26", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Thierry Calandra, Thierry Roger "}, {"type": "b", "children": [{"type": "t", "text": "Macrophage migration inhibitory factor: a regulator of innate immunity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Rev Immunol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nri1200"}], "href": "https://doi.org/10.1038/nri1200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14502271"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14502271"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Lin Leng, Christine N Metz, Yan Fang, et al. 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