Macrophage migration inhibitory factor (MIF) (MIF)

Macrophage migration inhibitory factor (MIF), also known as parthanatos-associated apoptosis-inducing factor (AIF) nuclease (PAAN), is a pleiotropic protein that functions as a cytokine, chaperone, and enzyme with nuclease, tautomerase, and thiol-oxidoreductase activities [2, 5, 12]. In the parthanatos cell death pathway, MIF acts as the final executioner by translocating to the nucleus in complex with AIF to fragment genomic DNA [3, 7, 8]. This pathway is highly relevant in neurodegenerative diseases such as Parkinson's and Alzheimer's, as well as acute neurological conditions like stroke and traumatic brain injury [3, 5, 6, 13]. MIF is also a key player in inflammatory diseases and cancer progression, where it modulates immune responses and promotes tumor growth [14, 16]. Therapeutic strategies include small-molecule inhibitors like PAANIB-1, which selectively targets the nuclease activity to provide neuroprotection, and other agents like Ibudilast and ISO-1 that inhibit its tautomerase or signaling functions [1, 5, 11, 14]. Targeting the specific nuclease activity of MIF is considered a promising approach to prevent neuronal loss while minimizing interference with its other physiological roles [6, 31].

Other names

Parthanatos-associated apoptosis-inducing factor nucleasePAANGlycosylation-inhibiting factorGIFGLIFMMIFPhenylpyruvate tautomeraseL-dopachrome isomerase

MIF inhibitors act by blocking the nuclease activity (preventing DNA fragmentation), inhibiting the tautomerase active site, disrupting the interaction between MIF and AIF, or antagonizing MIF receptors such as CD74 and CXCRs to prevent pro-inflammatory and pro-death signaling [3, 11, 22, 27].