Protein lactylation in cancer and other pathologies: Epigenetic regulation of glycolysis and its therapeutic perspectives

Abstract

Lactylation, a recently recognized post-translational protein modification, is reshaping research in epigenetics and molecular medicine. Emerging evidence indicates that lactylation plays a critical role in the onset and progression of cancer, as well as in several pre-cancerous and metabolism-associated pathologies. This review summarizes the current understanding of the mechanisms and biological roles of lactylation in cancer and other diseases. Lactate has been shown to promote carcinogenesis both as an additional energy source and as a signaling molecule. Glycolysis and glucose transport—major sources of lactate and subsequent lactylation—are frequently targeted by anti-cancer therapies. Several small-molecule glucose transporter type 1 (GLUT1) inhibitors, including STF-31, WZB-117, and BAY-876, have demonstrated efficacy in suppressing tumor growth. During lactylation, lactate is covalently attached to histone lysine residues, leading to epigenetic modifications. This process is regulated by “writer” enzymes (p300 and HBO1) and “eraser” enzymes (HDAC1–3 and SIRT1–3), which participate in nuclear signaling networks associated with oncogenic transformation. Several inhibitors targeting “writer” enzymes, such as A485 and andrographolide, have been developed and shown to suppress angiogenesis. Inhibition of tumor immune evasion has also been explored using glycolytic enzyme inhibitors, including 2-deoxy-D-glucose and oxalate. Despite these advances, lactylation-targeted research remains in its early stages and faces notable limitations that warrant further investigation. This review provides insights into the role of lactylation in diverse diseases and highlights emerging therapeutic strategies aimed at modulating lactylation-associated molecular targets.