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Itaconate, a metabolite of the tricarboxylic acid cycle, plays anti‐inflammatory roles in macrophages during endotoxemia. The mechanisms underlying its anti‐inflammatory roles have been shown to be mediated by the modulation of oxidative stress, an important mechanism of hepatic ischemia–reperfusion (I/R) injury. However, the role of itaconate in liver I/R injury is unknown.

We found that deletion of immune‐responsive gene 1 (IRG1), encoding for the enzyme producing itaconate, exacerbated liver injury and systemic inflammation. Furthermore, bone marrow adoptive transfer experiments indicated that deletion of IRG1 in both hematopoietic and nonhematopoietic compartments contributes to the protection mediated by IRG1 after I/R. Interestingly, the expression of IRG1 was up‐regulated in hepatocytes after I/R and hypoxia/reoxygenation‐induced oxidative stress …