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Multiple small molecule inhibitors of MIF have been described, including the clinically available anti-rheumatic drug T-614 (iguratimod); however, this drug\u2019s mode of inhibition has not been fully investigated.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We conducted in vitro testing including kinetic analysis and protein crystallography to elucidate the interactions between MIF and T-614. We also performed in vivo experiments testing the efficacy of T-614 in a murine model of acetaminophen toxicity. We analyzed survival in lethal APAP overdose with and without T-614 and using two different dosing schedules of T-614. We also examined MIF and MIF inhibition effects on hepatic hydrogen peroxide (H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>) as a surrogate of oxidative stress in non-lethal APAP overdose.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Kinetic analysis was consistent with a non-competitive type of inhibition and an inhibition constant (K<jats:sub>i<\/jats:sub>) value of 16 \u00b5M. Crystallographic analysis revealed that T-614 binds outside of the tautomerase active site of the MIF trimer, with only the mesyl group of the molecule entering the active site pocket. T-614 improved survival in lethal APAP overdose when given prophylactically, but this protection was not observed when the drug was administered late (6\u00a0h after APAP). T-614 also decreased hepatic hydrogen peroxide concentrations during non-lethal APAP overdose in a MIF-dependent fashion.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>T-614 is an allosteric inhibitor of MIF that prevented death and decreased hepatic hydrogen peroxide concentrations when given prophylactically in a murine model of acetaminophen overdose. Further studies are needed to elucidate the mechanistic role of MIF in APAP toxicity.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s10020-024-00803-0","type":"journal-article","created":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T15:01:29Z","timestamp":1711551689000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Iguratimod, an allosteric inhibitor of macrophage migration inhibitory factor (MIF), prevents mortality and oxidative stress in a murine model of acetaminophen overdose"],"prefix":"10.1186","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7654-7828","authenticated-orcid":false,"given":"Joshua","family":"Bloom","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios","family":"Pantouris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingzhu","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bayan","family":"Aljabari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lopa","family":"Mishra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramu","family":"Manjula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Parkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elias J.","family":"Lolis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yousef","family":"Al-Abed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,27]]},"reference":[{"key":"803_CR1","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1007\/PL00000291","volume":"51","author":"Y Aikawa","year":"2002","unstructured":"Aikawa Y, Yamamoto M, Yamamoto T, Morimoto K, Tanaka K. 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YA is an inventor or co-inventor for multiple other small molecule inhibitors of MIF. MH, BA, and YA are current staff at the Feinstein Institutes for Medical Research. JB received a stipend as a MD\/PhD candidate in the Zucker School of Medicine at Hofstra\/Northwell Health, and his PhD studies were completed at the Feinstein Institutes for Medical Research. The authors have no other potential conflicts of interest to declare.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"43"}}