Non-histone lactylation in cancer: current advances and clinical implications

Lactylation, a novel post-translational modification characterized by the covalent attachment of lactate to specific lysine residues, has emerged as a critical metabolic regulator in cancer. Initially linked to histone modification-mediated transcriptional control, recent advancements have expanded this paradigm by revealing widespread non-histone lactylation, which modulates protein stability, enzymatic activity, and interactions, thereby significantly impacting tumor proliferation, metastasis, and therapy resistance. Recent advances have uncovered several key enzymes driving lactylation, including lysine acetyltransferases and deacetylases, and novel "writers" like alanyl-tRNA synthetases, highlighting the complexity and diversity of lactylation mechanisms. This review synthesizes current advances in non-histone lactylation in cancer, emphasizing its regulatory mechanisms and functional impacts. We also discuss potential therapeutic strategies, such as small-molecule inhibitors and peptides targeting lactate-driven pathways. By integrating current evidence, this review underscores non-histone lactylation as a promising area for cancer research and management, offering new insights into the complex interplay between metabolism and tumor biology.