Neutrophil immunometabolism in ACLF and sepsis: mechanisms, dysfunction, and therapeutic opportunities

Innate immune cells, undergo profound metabolic changes in critical illnesses. In both, acute-on-chronic liver failure (ACLF) and sepsis, these alterations underpin the paradoxical coexistence of hyperinflammation and immune dysfunction.

Here, we present a comparative framework to examine how immune metabolic circuits are reshaped across these two syndromes. We focus primarily on neutrophil function while also considering contributions from other immune cell types, highlighting shared pathways, divergent mechanisms, and their clinical implications.

We first delineate shared features of neutrophil activation in critical illness, including glycolysis-driven metabolic reprogramming, excessive reactive oxygen species (ROS) generation, and neutrophil extracellular trap (NET) formation, all processes that amplify tissue injury and propagate systemic inflammation. However, fundamental differences emerge in the baseline immune state, trajectory, and underlying immunometabolic programming of the two diseases.

Sepsis arises as an acute insult in a previously homeostatic immune system, triggering a rapid transition from hyperactivation to mitochondrial dysfunction and eventual metabolic exhaustion.