Hexokinase 2-mediated gene expression via histone lactylation is required for hepatic stellate cell activation and liver fibrosis.

Lactate was implicated in the activation of hepatic stellate cells (HSCs). However, the mechanism by which lactate exerts its effect remains elusive. Using RNA-seq and CUT&Tag chromatin profiling, we found that induction of hexokinase 2 (HK2) expression in activated HSCs is required for induced gene expression by histone lactylation but not histone acetylation. Inhibiting histone lactylation by Hk2 deletion or pharmacological inhibition of lactate production diminishes HSC activation, whereas exogenous lactate but not acetate supplementation rescues the activation phenotype. Thus, lactate produced by activated HSCs determines the HSC fate via histone lactylation. We found that histone acetylation competes with histone lactylation, which could explain why class I HDAC (histone deacetylase) inhibitors impede HSC activation. Finally, 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.