Lysine lactylation in neutrophil functional remodeling across diverse disease contexts

Abstract

Lactate, traditionally regarded as a product of glycolytic metabolism, is increasingly recognized as a metabolite that can influence cellular signaling and protein post-translational modification, including lysine lactylation (Kla). Neutrophils rely on glycolytic metabolism to support rapid effector functions and encounter substantial metabolic changes during inflammation, infection, ischemic injury, and tumor progression. Emerging studies have implicated histone and non-histone lactylation in the regulation of neutrophil-associated processes, including migration, inflammatory activation, neutrophil extracellular trap (NET) formation, and functional phenotypic remodeling. However, the extent to which these effects are mediated directly by lactylation within neutrophils remains incompletely defined, as some available evidence derives from other cell types, tissue compartments, or indirect associations with neutrophil responses. In this review, we summarize current knowledge of the molecular mechanisms regulating lysine lactylation, with a focus on lactyltransferases, delactylases, and lactylation-associated reader proteins. We further examine evidence linking lactylation-associated signaling to neutrophil migration, NET formation, and functional heterogeneity across inflammatory, ischemic, and tumor-associated settings, with consideration of distinct neutrophil populations. We also discuss the potential interplay between lactylation and other lysine acylation modifications, as well as current methodological challenges in accurately detecting and quantifying Kla and distinguishing enzymatic from non-enzymatic lactylation. Finally, we evaluate emerging pharmacological and biomarker-based approaches targeting lactate metabolism and lactylation-associated pathways. Although these studies provide a growing framework for understanding how metabolic alterations may influence neutrophil function, most evidence remains preclinical or indirect, and the relative contribution of lactylation to neutrophil responses across different pathological contexts remains to be established. Further studies using site-specific quantitative approaches, primary human neutrophils, and neutrophil-specific genetic or mechanistic models will be required to define the causal and context-dependent roles of lysine lactylation in neutrophil biology.