Positive feedback between histone H4K16 lactylation and glycolysis promotes MAFLD progression

Metabolic-associated fatty liver disease (MAFLD) is a progressive metabolic disorder characterized by hepatic steatosis, inflammation, and fibrosis. Emerging evidence suggests that lactate-driven histone lactylation may contribute to its pathogenesis, but mechanisms remain unclear.

C57BL/6 mice were fed HFD or CDHFD, and hepatocytes were treated with OAPA. Histone lactylation was assessed by IF and WB. CUT&Tag and RNA-seq identified downstream targets, while H4K16R mutation, PDK4 knockdown, and dichloroacetic acid (DCA) inhibition were applied in vitro and in vivo.

Histone lactylation, especially H4K16la, was elevated in murine and human MASH and correlated with steatosis, inflammation, and fibrosis. H4K16la directly activated PDK4 transcription, forming a lactate-H4K16la-PDK4 feedback loop that exacerbated MAFLD. Genetic or pharmacologic inhibition reduced lactate, lipid accumulation, and liver injury.

We identify a lactate-H4K16la-PDK4 axis that drives metabolic reprogramming and MAFLD progression. Targeting PDK4 may represent a therapeutic strategy for MAFLD/MASH.