Lysine lactylation-modifying enzymes: The bridge between cellular metabolism and epigenetic regulation

In recent years, protein lysine lactylation (Kla) has emerged as a pivotal and rapidly expanding post-translational modification (PTM), serving as a dynamic metabolic sensor that directly couples cellular lactate flux to epigenetic regulation. Functioning as a direct molecular bridge between metabolism and signaling, Kla is uniquely driven by glycolytic activity to orchestrate transcriptional and functional reprogramming across diverse physiological and pathological contexts. The enzymatic machinery governing Kla—comprising writers, erasers, and readers—exhibits remarkable plasticity and specificity, modulated by metabolic signals (e.g., lactate, ATP, NAD⁺), crosstalk with other PTMs, and intricate signaling networks. Dysregulation of these enzymes is increasingly implicated in a spectrum of diseases, including sepsis, cancer, neurodegenerative disorders, and metabolic syndromes, highlighting their potential as therapeutic targets. This review provides a comprehensive overview of the current understanding of Kla-modifying enzymes, systematically categorizing their functional roles, substrate specificity, subcellular localization, and regulatory mechanisms. We further elucidate their pathological contributions to disease progression and propose an integrative framework for targeting the Kla-metabolism-epigenetics axis, offering novel insights for translational research and therapeutic innovation across biomedical disciplines.