Histone lactylation in hepatocellular carcinoma: a key epigenetic hub linking metabolic reprogramming and the immune microenvironment

Abstract

Hepatocellular carcinoma (HCC) is a malignant tumor with extremely high global morbidity and mortality. Its initiation and progression are tightly associated with the complex tumor microenvironment (TME), which drives immune escape and treatment resistance in liver cancer. In recent years, epigenetic regulation, particularly histone modification mediated by cellular metabolism, has emerged as a critical advance in deciphering tumor malignant behavior and its interaction with the microenvironment. Histone lactylation, a newly identified post-translational modification directly mediated by lactate, offers a novel perspective for understanding how abnormal tumor metabolism (especially the Warburg effect) shapes the immune microenvironment via epigenetic reprogramming. This review elaborates on the role of histone lactylation in HCC progression, focusing on its mechanisms in regulating oncogenic signaling pathways, metabolic reprogramming and reshaping the HCC TME, thereby serving as a core node in metabolic-epigenetic-immune crosstalk. In addition, we summarize the intervention strategies and drug development targeting this modification, and discuss future directions, aiming to provide a basis for the development of novel HCC therapeutic strategies based on metabolic-epigenetic regulation.

Keywords

Hepatocellular carcinoma / tumor microenvironment / glycolysis / histone lactylation / epigenetic modification / metabolic reprogramming

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