Immune Regulation of Itaconate and Its Derivatives in Liver Diseases.

Abstract

Over the past few decades, liver disease has emerged as one of the leading causes of death worldwide. Liver injury is frequently associated with infections, alcohol consumption, or obesity, which trigger hepatic inflammation and ultimately lead to progressive fibrosis and carcinoma. Although various cell populations contribute to inflammatory and fibrogenic processes in the liver, macrophages serve as a pivotal mediator. Hepatic macrophages exhibit substantial heterogeneity and perform diverse functions that depend on the pathological microenvironment. The immune response gene 1 (IRG1), a critical metabolic regulatory gene, encodes the mitochondrial enzyme aconitate decarboxylase 1 (ACOD1), which influences macrophage functional polarization by promoting the synthesis of itaconate, a metabolite produced via a side pathway of the tricarboxylic acid (TCA) cycle. Increasing evidence indicates that itaconate and its derivatives exert immunomodulatory effects in processes such as oxidative stress, viral infection, inflammation, tumorigenesis, and wound healing, thereby demonstrating significant potential for treating liver disorders. In this review, we summarize the roles of itaconate and its derivatives in liver diseases and their underlying mechanisms, thereby providing insights into the therapeutic potential of targeting macrophages.