Pyruvylation expands the redox repertoire of lysine acylation.

Song et al. establish lysine pyruvylation (Kpy) as an acylation response to glycolytic flux and pyruvate availability, detect pyruvyl-CoA, implicate histone acetyltransferase 1 and p300 as writers and sirtuin 3 as an eraser, and link promoter-associated histone Kpy to transcriptional regulation, defining a distinct C3 acylation alongside lactylation at the redox-coupled pyruvate-lactate node.