Analysis of Immunometabolic Profiles in Patients With Chronic Drug-Induced Liver Injury and Validation in Mice to Reveal Potential Mechanisms.

Abstract

Background: The mechanism underlying chronic drug-induced liver injury (DILI) remains unclear. Immune activation is a common feature of DILI progression and is closely associated with metabolism. We explored the immunometabolic profile of chronic DILI and the potential mechanism of chronic DILI progression.

Methods: Plasma and peripheral blood mononuclear cells from patients with chronic DILI were analyzed using multiplex immunoassays and untargeted metabolomics to reveal their immunometabolic profile. The effects and potential mechanisms of chronic DILI-related metabolite on acute or chronic liver injury induced by LPS or CCl₄ in mice were investigated.

Results: Patients with chronic DILI exhibited elevated plasma IL-6, IL-12p70, IL-15 and reduced IL-10 levels. The percentage of IL-12⁺ monocytes was higher, while that of CD206⁺ monocytes, IL-10⁺ monocytes, Th2, Treg, and IL-10⁺ CD4⁺ T cells were lower in patients with chronic DILI compared to those with acute DILI. We identified the most significantly increased metabolite in patients with chronic DILI was cis-aconitic acid (CAA). Administration of CAA can attenuate liver injury in mice with acute liver injury induced by LPS or CCl₄ and promote the spontaneous resolution of liver fibrosis in mice with chronic live injury induced by CCl₄. The protective mechanism of CAA against liver injury is associated with the inhibition of hepatic macrophage infiltration and polarization, which is achieved by inhibiting the secretion of neutrophil-derived IL-33 and subsequent phosphorylation of GATA3.

Conclusions: CAA, which is elevated in patients with chronic DILI, protects against liver injury by inhibiting hepatic macrophage infiltration and polarization through the suppression of the IL-33/GATA3 pathway, suggesting that CAA may serve as a potential target for regulating tissue repair in liver injury.