Integrating lipidomics and network pharmacology reveals Valproic acid remodels the lipid metabolic microenvironment in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is characterized by lipid metabolic reprogramming. Valproic acid (VPA), a widely used antiepileptic drug known to modulate lipid homeostasis, has shown potential anti-HCC activity; however, its impact on lipid remodeling and the underlying mechanism remains unclear. We employed an integrated approach combining lipidomics, network pharmacology, molecular docking, and molecular dynamics simulations to investigate this. In HepG2 tumor-bearing mice, VPA dose-dependently inhibited tumor growth. Lipidomics identified 210 and 98 differential lipids in the 250 mg/kg and 500 mg/kg groups, respectively, primarily enriched in glycerophospholipid and choline metabolism, with 17 overlapping species in both groups. Target screening revealed 127 lipid metabolism-related targets of VPA in HCC, including 10 core targets such as PLA2G10, LCAT, and PON1. Docking and dynamics simulations confirmed stable VPA-LCAT binding, supported by functional evidence of elevated PC/LPC ratio and reduced cholesterol esterification. These findings demonstrate that VPA significantly remodels the lipid metabolic microenvironment in HCC, and these multifaceted changes offer new insights into its anti-HCC mechanisms.