Metabolite-driven protein modifications in immune signaling: from established principles to emerging pyruvylation

Immune signaling is tightly coupled to cellular metabolic state. Beyond supplying energy, metabolites can directly regulate immune responses by driving post-translational modifications of proteins and chromatin, shifting immunometabolism toward a model in which metabolic state encodes signaling outputs.

Protein pyruvylation has recently emerged as a metabolite-responsive lysine modification linking glycolytic metabolism to both immune signaling and transcriptional regulation. Established examples, including histone lactylation and acylation marks linked to acetyl-CoA and crotonyl-CoA, illustrate how metabolite availability shapes chromatin state and transcriptional competence. A recent Cell study showed that high glucose-enhanced glycolysis and pyruvate kinase M2 activity promotes STAT1 pyruvylation at Lys201, thereby disrupting STAT1-STAT2 interaction and suppressing type I interferon signaling. Complementing this signaling-centered mechanism, a subsequent Nature Metabolism study systematically characterized a broader lysine pyruvylation landscape, identified histone and non-histone substrates, linked pyruvylation to glycolytic flux and pyruvyl-CoA metabolism, and implicated HAT1 and p300 as pyruvylation writers and SIRT3 as an eraser. Together, these findings expand pyruvylation from a single signaling event into an emerging metabolite-responsive regulatory system operating across protein signaling and chromatin-associated transcriptional control. In this review, we summarize the conceptual framework of metabolite-driven protein modifications, compare established marks, and discuss the remaining questions surrounding pyruvylation chemistry, enzyme and substrate specificity, reader mechanisms, compartmentalization, detection strategies, physiological relevance, and potential immunopharmacological implications.

Metabolite-driven protein modifications represent an important regulatory layer linking metabolic rewiring to immune reprogramming. Elucidating the chemistry, regulatory machinery, substrate landscape, and physiological functions of pyruvylation will not only advance our understanding of immunometabolism but may also facilitate the development of metabolite-based biomarkers and therapeutic strategies for inflammatory and immune-related disease.