Ginsenoside RK1 Promotes Hepatic Stellate Cell Glycolysis-Mediated Ferroptosis by Activating the HK2/ACSL4/LPCAT3/ALOX5 Signaling Pathway

Liver fibrosis (LF) is a pathological condition that, if not controlled, can progress into liver sclerosis and malignant tumors. Ferroptosis has been comprehensively studied and found to improve LF by exacerbating hepatic cell ferroptosis. Ginsenoside RK1 (GRK1) is an essential component of ginseng with antifibrotic effects. However, the anti-LF mechanism of GRK1 remains elusive. The impact of GRK1 on LF was evaluated via RNA-sequence analysis of GRK1-treated hepatic stellate cells (HSC). Furthermore, a cellular thermal shift assay, drug affinity-responsive target stability, and molecular docking analyses were carried out to verify the interaction between GRK1 and HK2. The fibrosis indicators and histopathology assessment revealed that GRK1 substantially suppressed CCl4-induced LF in mice. Moreover, GRK1 markedly improved malondialdehyde, lipid reactive oxygen species, and liver Fe2+ in CCl4-stimulated mice. This study revealed that GRK1 targets HK2 in HSC-T6 cells to stimulate the ACSL4/LPCAT3/ALOX5 pathway, thereby inducing HSC ferroptosis and alleviating hepatic fibrosis.