Lysine lactylation in diseases: beyond histone lactylation

Abstract Lactylation, a recently identified post-translational modification, was initially characterized as lysine residue modification in histone subunits that regulates gene transcription via epigenetic mechanisms. Elevated intracellular lactate has been shown to drive histone lysine lactylation (Kla), establishing its association with disease pathogenesis. Emerging evidence reveals that Kla modifications extend beyond histones to transcriptional regulators and cytoplasmic functional proteins. Unlike the broad transcriptional regulation mediated by histone lactylation, Kla modifications of functional proteins exert regulatory effects through both specific transcriptional modulation and direct functional alteration of target proteins, thereby precisely controlling biological processes. This review systematically examines the pathological implications of Kla modifications of functional proteins across multiple disease contexts, including inflammatory disorders, infectious diseases, neurological or cardiovascular pathologies, and oncological conditions. Our synthesis provides mechanistic insights into disease-associated Kla networks, facilitating therapeutic target discovery and pharmacological intervention strategies.