Limonin Is a Novel Hexokinase 2 Inhibitor That Suppresses Hepatic Stellate Cell Activation and Histone Lactylation.

Hexokinase 2 (HK2) is a pivotal enzyme in glycolytic metabolism and plays a crucial role in the activation of hepatic stellate cells (HSCs). Despite its importance, specific inhibitors targeting HK2 are still lacking in clinical practice. In this study, we utilized a human protein microarray to identify a significant interaction between limonin (Lim) and HK2. Subsequent analyses confirmed that Lim effectively inhibits HK2 activity and the modification of histone lactylation. Moreover, Lim's systemic effects include the downregulation of gene expression associated with HSC activation, which is closely linked to its modulation of HK2 and histone lactylation. Additionally, Lim exhibits anti-fibrotic properties, influencing the expression of genes involved in HSC activation and histone lactylation in vivo. These findings provide novel mechanistic insights into how Lim derivatives may mitigate hepatic fibrosis through the suppression of HK2 and targeted regulation of histone lactylation in activated HSCs.