Itaconate reduces LPS/GaIN-induced hepatocyte necroptosis by inhibiting ROS-PAD4-mediated extracellular traps of macrophages.

Acute liver failure (ALF) is a critical syndrome characterized by massive hepatocyte death, yet the role of macrophage extracellular traps (METs) in its pathogenesis remains poorly defined. This study investigated the effect and mechanism of the immunometabolite itaconate on MET formation and hepatocyte necroptosis in LPS/D-GaIN-induced ALF. We found that MET release was significantly elevated in ALF mice and in LPS-stimulated macrophages. Scavenging reactive oxygen species (ROS) inhibited PAD4-mediated MET extrusion. Furthermore, METs promoted hepatocyte necroptosis by activating the RIPK1/RIPK3/MLKL pathway. Genetic deletion of Irg1 (encoding the itaconate-synthesizing enzyme ACOD1) exacerbated MET formation, inflammation, and liver injury, whereas 4-OI treatment conferred significant protection. Our findings reveal a novel pathogenic axis in ALF wherein itaconate inhibits ROS-PAD4-driven MET release to attenuate hepatocyte necroptosis, highlighting a potential therapeutic strategy for acute liver injury.