The dual faces of lactylation: From post-translational modification to disease regulation

Lactate, long regarded as the terminal product of glycolysis, is now recognized as a signaling metabolite that shapes diverse physiological and pathological processes. Lysine lactylation, a recently identified post-translational modification (PTM), has emerged as a key regulator of disease onset and progression. Acting as a double-edged sword, lactylation can either promote pathogenic signaling or facilitate tissue repair, depending on cellular context. These opposing actions highlight its potential as a precise therapeutic target. In this review, we examine the functions of lactate recognition proteins that mediate lactate uptake, transport, and lactylation-associated enzymatic activity. We further detail how histone and non-histone lactylation regulate essential biological processes, including glycolysis-linked cellular functions, RNA modification, macrophage polarization, and cell-fate determination. Finally, we discuss the relationship between lactylation and other modifications, such as acetylation, and provide a forward-looking perspective on the pathophysiological significance of lactylation.