Lysine pyruvylation: decoding the molecular language of pyruvate signaling

Lysine pyruvylation (Kpy) converts pyruvate availability into a reversible protein modification, placing a central carbon metabolite directly within cellular regulatory circuits. An initial study identified STAT1 K201 pyruvylation and showed that this modification suppresses type I interferon signaling by disrupting STAT1–STAT2 assembly. A subsequent study established HAT1 and p300 as Kpy writers and SIRT3 as a Kpy eraser, linking histone Kpy to glycolytic flux, active chromatin and transcription. Together, these findings introduce Kpy as a potential interface between metabolism, chromatin and immunity. However, evidence is currently limited to two initial mechanistic studies: disease causality, abundance and occupancy in human tissues, and translational utility remain unestablished. This commentary therefore distinguishes demonstrated mechanisms from testable hypotheses and outlines the evidence required before Kpy can be considered a disease biomarker or therapeutic target. In this Comment article, Jun Zhang discusses the emerging role of lysine pyruvylation as a metabolic regulator and outlines the key evidence needed to establish its relevance as a biomarker and therapeutic target in human disease.