6-Gingerol alleviates hepatic fibrosis via inhibiting glycolytic reprogramming by targeting IGF2BP2

Hepatic fibrosis remains a major global health burden, often progressing to cirrhosis and hepatocellular carcinoma. Despite extensive research, no effective antifibrotic drugs are clinically approved due to the complexity of hepatic stellate cells (HSCs) activation and metabolic remodeling. Enhanced glycolysis is increasingly recognized as a metabolic hallmark sustaining the profibrotic phenotype of HSCs, representing a key but underexplored therapeutic target. This study explored the antifibrotic effect of 6-gingerol, the principal bioactive compound of Zingiber officinale, and revealed its novel mechanism involving metabolic-epitranscriptomic regulation of HSC activation.

Liver fibrosis was induced in C57BL/6 mice by carbon tetrachloride (CCl₄) and bile duct ligation (BDL), followed by oral 6-gingerol treatment. Complementary in vitro studies were performed in transforming growth factor-β1 (TGF-β1)-stimulated Lieming Xu-2 (LX-2 cells, a human hepatic stellate cell line) and primary HSCs from liver fibrosis mice. Integrated transcriptomics, network pharmacology, molecular docking, and cellular thermal shift assays (CETSA) were combined with functional genetic manipulation to identify and verify molecular targets.

6-Gingerol alleviated hepatic injury and collagen deposition in both CCl₄- and BDL-induced models and improved liver function. Mechanistically, 6-gingerol inhibited glycolysis by downregulating hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA), normalizing pyruvate and lactate metabolism, and restoring mitochondrial respiration. Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) was identified as an important mediator associated with glycolytic enzyme expression and HSCs activation, and its silencing abolished 6-gingerol's antifibrotic effects.

Our study demonstrates that 6-gingerol attenuates hepatic fibrosis by targeting IGF2BP2-dependent glycolytic reprogramming, thereby restoring metabolic homeostasis and inhibiting HSCs activation. These findings uncover a novel metabolic-epitranscriptomic mechanism and suggest that 6-gingerol represents a promising therapeutic strategy for chronic liver diseases.