Neutrophil metabolic heterogeneity as a novel target in diseases

Neutrophils, pivotal effector cells of the immune system, are increasingly recognized to have considerable functional and phenotypic heterogeneity. The emergence of immunometabolism has offered a framework for understanding this diversity. Accumulating evidence indicates that shifts in metabolic pathways and their byproducts can reshape the fate and function of neutrophils. Neutrophil heterogeneity arises from both distinct developmental stages and specific signals within peripheral tissue microenvironments. Functionally, glycolysis is the central metabolic pathway that fuels core effector responses, while metabolites such as lactate, lipids, and amino acids can further modulate neutrophil phenotypes. In pathological contexts of metabolic dysregulation, metabolic stress induces extensive reprogramming of neutrophils. This process drives the accumulation of specific metabolites, which in turn trigger transcriptional reprogramming through epigenetic remodeling, establishing a self-reinforcing loop that sustains pro-pathological neutrophil states. Targeting key nodes within these dysregulated metabolic pathways has potential as a therapeutic strategy. Here, we review the metabolic heterogeneity of neutrophil subpopulations and the mechanisms by which distinct metabolic programs drive disease progression in pathological settings. We further discuss current therapeutic strategies targeting these pathways. Through this analysis, we aim to provide a refined perspective on the immune landscape and to identify new possibilities for therapeutic intervention.