Vol. 1 No. 3 (2025): Lactylation: A Pivotal Metabolic-Epigenetic Nexus Driving Hepatocellular Carcinoma Pathogenesis and Therapeutic Resistance

Hepatocellular Carcinoma (HCC) remains a formidable global health challenge, characterized by its complex
etiology, aggressive progression, and high mortality rates. Metabolic reprogramming is a hallmark of cancer,
and lactate, a key end-product of glycolysis, has emerged as more than just a metabolic waste product. Recent
groundbreaking research has unveiled lactate’s role as a signaling molecule through a novel Post-Translational
Modification (PTM) known as lactylation. Protein lactylation, particularly histone lactylation, directly links cellular
metabolism to epigenetic regulation, profoundly influencing gene expression, protein function, and cellular
phenotypes. In the context of HCC, an increasing body of evidence highlights the widespread and critical
involvement of lactylation in various pathological processes, including tumor initiation, progression, metastasis,
immune evasion, and therapeutic resistance. This comprehensive review synthesizes the current understanding
of protein lactylation in HCC, detailing its intricate mechanisms, diverse functional roles in metabolic