The Role of Hexokinase 2 in the Regulation of Histone Lactylation

Lactate, previously considered as a metabolic waste product, has been implicated in the induction of gene expression in activated hepatic stellate cells (HSCs). However, the mechanism by which lactate exerts its effect remains unknown. We demonstrate that the catalytic activity of hexokinase 2 (HK2) is sufficient to alter gene expression by histone lactylation but not histone acetylation. Using RNA-seq and CUT&Tag chromatin profiling, we found that induction of HK2 expression in activated HSCs is required for the induction of gene expression in activated HSCs via an increase in histone lactylation. Inhibiting histone lactylation through genetic deletion of Hk2 or pharmacological inhibition of lactate production diminishes HSC activation, whereas exogenous lactate supplementation, but not acetate supplementation, restores the activation phenotype. Thus, lactate produced by activated HSCs determines the HSC fate via histone lactylation. We also found that histone acetylation and lactylation are in competition, which could explain why class I HDAC inhibitors impede HSC activation and subsequent gene expression. Lastly, we found that HSC-specific or systemic deletion of Hk2 inhibits HSC activation and liver fibrosis in vivo. Therefore, we provide evidence that HK2 may be an effective therapeutic target for liver fibrosis.