Hepatology international · 2025
Positive feedback between histone H4K16 lactylation and glycolysis promotes MAFLD progression.
СтатьяНазвание и аннотация: Перевод в очереди
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Jiao Qinlian, Ren Yidan, Teng Xiaoyu, Feng Maoxiao, Liu Xiaoyan, Cai Yuxuan, Hu Tangbin, Wang Mo, Wang Yunshan
Аннотация
BACKGROUND/AIMS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: We identify a lactate-H4K16la-PDK4 axis that drives metabolic reprogramming and MAFLD progression. Targeting PDK4 may represent a therapeutic strategy for MAFLD/MASH.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: We identify a lactate-H4K16la-PDK4 axis that drives metabolic reprogramming and MAFLD progression. Targeting PDK4 may represent a therapeutic strategy for MAFLD/MASH.