The emerging role of protein L-lactylation in metabolic regulation and cell signalling.

L-Lactate has emerged as a crucial metabolic intermediate, moving beyond its traditional view as a mere waste product. The recent discovery of L-lactate-driven protein lactylation as a post-translational modification has unveiled a pathway that highlights the role of lactate in cellular signalling. In this Perspective, we explore the enzymatic and metabolic mechanisms underlying protein lactylation and its impacts on both histone and non-histone proteins in the contexts of physiology and diseases. We discuss growing evidence suggesting that this modification regulates a wide range of cellular functions and is involved in various physiological and pathological processes, such as cell-fate determination, development, cardiovascular diseases, cancer and autoimmune disorders. We propose that protein lactylation acts as a pivotal mechanism, integrating metabolic and signalling pathways to enable cellular adaptation, and highlight its potential as a therapeutic target in various diseases.