Ya'NAn Chen

Background: Valproic acid (VPA)-induced hepatotoxicity is among the most common and severe adverse drug reactions, limiting its clinical application. Recent studies have suggested that activating the farnesoid X receptor (FXR) could be a promising therapeutic approach to alleviate VPA-induced hepatotoxicity; however, related research remains limited. Objective: This study aims to comprehensively investigate the mechanisms underlying FXR activation by obeticholic acid (OCA) for the treatment of VPA-induced hepatotoxicity. Methods: Network pharmacology was performed to identify potential targets and pathways underlying the amelioration of VPA-induced hepatotoxicity by OCA. The identified pathways were validated through GEO data analysis, and the affinities between OCA and potential key targets were predicted using molecular docking as well as molecular dynamics simulations. Results: A total of 462 targets associated with VPA-induced hepatotoxicity and 288 targets of OCA were identified, with 81 shared targets. KEGG pathway and GO enrichment analysis indicated that the effect of OCA on VPA-induced hepatotoxicity primarily involved lipid metabolism, as well as oxidative stress and inflammation. The results from GEO data analysis, molecular docking, and molecular dynamics simulations revealed a close association between bile secretion, the PPAR signaling pathway, and the treatment of VPA-induced hepatotoxicity by OCA. Conclusion: Our findings suggest that OCA exhibits potential therapeutic efficacy against VPAinduced hepatotoxicity through multiple targets and pathways, thereby highlighting the therapeutic potential of FXR as a target for treating VPA-induced hepatotoxicity.

Valproic acid (VPA), a classic antiepileptic drug with a narrow therapeutic window, is widely used in paediatric epilepsy treatment. As only the unbound fraction of the drug is a pharmacologically active component, we established a population pharmacokinetic (PopPK) model for both unbound and total VPA in epileptic children to provide a clinical optimisation strategy. A total of 450 epileptic children providing 620 samples were included for modelling development. In addition, trough unbound and total VPA concentrations were simulated for typical patients to propose the dose regimen. A one‐compartment model with first‐order absorption and elimination was well developed to describe the pharmacokinetic characteristics of unbound VPA, and the Langmuir equation was used to explore the protein binding parameters. The final model indicated that the CL _u /F of unbound VPA was significantly influenced by body weight, age‐based maturation and daily dose. Proposed dosing regimens for children aged 0 to 12 years, simulated using the Monte Carlo method, recommended 10–30 mg/kg/day, decreasing with age. This PopPK model of VPA could be helpful to propose recommended dosage regimens to achieve the target therapeutic concentration window in clinical practice.

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.