Valproic Acid Exacerbates Lipid Accumulation in High‐Fat Hepatocytes Induced by Oleic Acid: Insights From Lipidomic Analysis

Metabolic dysfunction-associated steatotic liver disease (MASLD) and valproic acid (VPA)-induced hepatotoxicity both involve dysregulated lipid metabolism. However, the specific effects of VPA on lipid metabolism in the context of MASLD remain unclear. This study aimed to investigate alterations in the lipid profile following VPA treatment using an oleic acid (OA)-induced cellular model of MASLD. After VPA treatment, non-targeted lipidomic analysis was performed. The results showed that VPA exacerbated lipid dysregulation by significantly increasing triglyceride (TAG) levels and promoting the accumulation of long-chain free fatty acids (FFAs) with carbon chain lengths between C20 and C26 in steatotic hepatocytes. Additionally, a positive correlation was observed between elevated TAG levels and the length of TAG carbon chains in VPA-treated steatotic hepatocytes. Disruptions in the homeostasis of phosphatidylethanolamines (PEs), lysophosphatidylethanolamines (LPEs), phosphatidylinositols (PIs), and sphingomyelins (SMs) were also observed. These findings indicate that VPA exacerbates lipid accumulation in steatotic hepatocytes, clarifying its role in worsening MASLD and highlighting the importance of risk-benefit assessment and hepatic monitoring in clinical management.