The role of protein lactylation: A kaleidoscopic post-translational modification in cancer

The recently discovered lysine lactylation represents a critical post-translational modification with widespread implications in epigenetics and cancer biology. Initially identified on histones, lysine lactylation has been also described on non-histone proteins, playing a pivotal role in transcriptional activation, protein function, and cellular processes. Two major sources of the lactyl moiety have been currently distinguished: L-lactyl-CoA (precursor of the L-lactyl moiety) and S-D-lactylglutathione (precursor of the D-lactyl moiety), which enable enzymatic and non-enzymatic mechanisms of lysine lactylation, respectively. Although the specific writers, erasers, and readers of this modification are still unclear, acetyltransferases and deacetylases have been proposed as crucial mediators of lysine lactylation. Remarkably, lactylation exerts significant influence on critical cancer-related pathways, thereby shaping cellular behavior during malignant transformation and the metastatic cascade. Hence, as recent insights into lysine lactylation underscore its growing potential in tumor biology, targeting this modification is emerging as a significant opportunity for cancer treatment. Lysine lactylation affects histone and non-histone proteins, influencing gene expression and protein function. Increasing studies in this field are revealing the lactyl-moiety sources, alongside its modulating enzymes. In addition, the crucial role of lactylation in cancer progression is coming to light, providing interesting breakthroughs in anti-cancer therapy.