Histone lactylation: A key epigenetic modulator in the pathogenesis of metabolic dysfunction-associated steatohepatitis and alcoholic steatohepatitis

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) and alcoholic steatohepatitis (ASH) are severe forms of chronic liver disease, characterized by inflammation, oxidative stress, lipid dysregulation, and fibrosis. Epigenetic changes, including acetylation, methylation, phosphorylation, ubiquitination, sumoylation, and lactylation of histones, dynamically regulate gene expression by altering the chromatin structure. Emerging evidence highlights histone modifications as chief contributors to the pathogenesis of chronic liver diseases. Lactylation which is a novel post-translational modification (PTM) of histone, has been observed as a crucial contributor to liver physiology as well as pathobiology. This modification, characterized by the addition of lactate to lysine residues on histones, influences gene expression and cellular metabolism in the liver. Intriguingly, elevated lactate levels in the liver, resulting from either chronic alcohol consumption or a high-fat/fructose-rich diet, may promote histone lactylation, particularly at histone 3 at lysine 18 (H3K18), which facilitates the transcription of pro-inflammatory and fibrogenic genes. This process not only intensifies hepatic inflammation and fibrosis but also disrupts normal metabolic pathways, resulting in further liver damage. This review aims to elucidate the role of histone lactylation in MASH. Although a direct demonstration of histone lactylation in ASH has not yet been reported, the altered lactate metabolism in ASH suggests that histone lactylation may significantly contribute to its pathogenesis. Finally, we explore novel strategies targeting histone lactylation to mitigate liver injury and improve disease management in MASH and ASH.

Keywords: Histone lactylation; Metabolic dysfunction-associated steatohepatitis; Alcoholic steatohepatitis; Epigenetics; Lactate

Core Tip: This review article describes a biological process called histone lactylation and its role in liver diseases. Histone lactylation is a metabolically aligned epigenetic modification on histones, which can regulate hepatic gene expression. Increased lactate levels in metabolic dysfunction-associated steatohepatitis and alcoholic steatohepatitis may induce histone lactylation of key genes involved in hepatic lipogenesis, inflammation and fibrosis. Consequently, pharmacological modulation of histone lactylation may open a new therapeutic option to counter metabolic dysfunction-associated steatohepatitis and alcoholic steatohepatitis progression.