Reprogramming Glucose Metabolism of Macrophage for Acute Liver Failure Therapy with Itaconate Lipo-Nanodrug.

Abstract

Acute liver failure (ALF) is a life-threatening disease featuring comprehensive inflammatory response and metabolic disorders in which macrophages exert central roles. A glucose metabolism mediator of macrophages, itaconate, has demonstrated potent anti-inflammatory efficacy in various diseases, implying that itaconate could work in treating ALF. However, systemic administration of itaconate may lead to immune disorder, making targeting the delivery of itaconate to the liver lesion area highly important. Herein, a liposomal nanodrug incorporating itaconate is developed, and its potential in treating acute liver failure in an ALF murine model established by LPS/D-GalN administration is tested. The nanodrug shows preferential liver accumulation to effectively alleviate LPS/D-GalN-induced hepatic histopathological injury by decreasing oxidative stress. Moreover, it reprograms the glucose metabolism of macrophages, resulting in macrophage repolarization toward the anti-inflammatory phenotype. Furthermore, western-blot and immunohistochemical assays verifies that the nanodrug may inhibit aerobic glycolysis of macrophages in an NRF2 and STING-dependent manner. These results underline the promise of the nanodrug for ALF treatment by reprogramming glucose metabolism.