Itaconate alleviates LPS-induced septic liver injury by regulating ROS-PAD4-mediated macrophages extracellular traps through Nrf2.

Abstract

Activated macrophages release macrophage extracellular traps (METs), which are a major cause of tissue damage in sepsis. However, the molecular mechanisms governing their production remain poorly characterized. In this study, we demonstrate that MET levels are markedly elevated in both the liver and circulation in a lipopolysaccharide (LPS)-induced sepsis model. The immunometabolite itaconate-a product of the enzyme aconitate decarboxylase 1 (Acod1)-emerged as a critical suppressor of this pathway. Genetic ablation of immune responsive gene 1 (Irg1) resulted in heightened MET release, exacerbated hepatic injury, and decreased survival in septic mice. In contrast, the itaconate derivative 4-octyl itaconate (4-OI) robustly suppressed MET formation and ameliorated liver damage. Mechanistically, 4-OI activated the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), resulting in scavenging of intracellular reactive oxygen species (ROS), which suppressed ROS-dependent activation of peptidylarginine deiminase 4 (PAD4), thereby inhibiting histone citrullination and subsequent MET release. The suppression of MET formation by 4-OI is mediated through an Nrf2-dependent mechanism, as its absence abolishes this suppression, revealing the Nrf2-ROS-PAD4 axis's key role. The findings reveal a new metabolic-immune pathway: itaconate reduces sepsis-linked liver injury by using Nrf2 to suppress METs, suggesting a novel clinical treatment approach.

Key Findings

• Itaconate suppresses macrophage extracellular trap (MET) formation in LPS-induced sepsis.
• 4-octyl itaconate (4-OI) activates Nrf2, leading to scavenging of ROS and inhibition of PAD4 activation.
• Nrf2-dependent suppression of ROS-PAD4 axis reduces liver injury and improves survival in septic mice.

Clinical Significance

Citation

Zeng Liwu, Wang Yaxin, Mao Ganet al.. Itaconate alleviates LPS-induced septic liver injury by regulating ROS-PAD4-mediated macrophages extracellular traps through Nrf2. Inflammation research : official journal of the European Histamine Research Society ... [et al.]. 2026-Sep-05.