Lactylation in the regulation of macrophage polarization: Mechanisms pathophysiological significance (Review)

Macrophage polarization is regulated by metabolic reprogramming epigenetic modifications.The discovery of histone lysine lactylation has revealed that lactate is not merely a glycolytic end product but also an important metabolic signal linking cellular metabolic status to gene expression programs.Lactylation modulates both histones (such as H3K18la) non-histone proteins (such as nuclear factor-κB p65 hypoxia-inducible factor-1α), thereby influencing macrophage polarization through transcriptional regulation signal transduction.Its functions are highly context-dependent.In the tumor microenvironment, it predominantly promotes M2-type immunosuppression; in certain neuroinflammatory conditions, it may be associated with M1-like phenotypes; in metabolic diseases, it may exacerbate pro-inflammatory damage.This modification involves extensive crosstalk with acetylation, methylation, other epigenetic modifications, constituting a complex regulatory network.However, current research faces critical bottlenecks: The intracellular source metabolic flux of lactyl-CoA remain unclear; the substrate specificity physiological relevance of candidate writers, such as E1A-binding protein p300 creB-binding protein, erasers, such as sirtuin 2, remain controversial; a bona fide reader domain that specifically recognizes lactylated lysine has not been identified; in vivo causal evidence remains limited.Future efforts should integrate multiomics technologies, genetic manipulation tools, precision delivery systems to decipher the spatiotemporal regulatory networks of lactylation, thereby facilitating the identification of new therapeutic targets strategies for inflammatory, neoplastic, metabolic diseases.