Valproic acid: Mechanistic insights into neuronal actions, epigenetic modulation, and clinical risk

Valproic acid (VPA), a branched-chain aliphatic carboxylic acid, has been a cornerstone of neuropsychiatric therapeutics for over five decades. While initially developed as an anticonvulsant, VPA has demonstrated pharmacodynamic versatility across a broad spectrum of disorders, including bipolar affective disorder, migraine prophylaxis, and emerging applications in oncology and neurodegeneration. Mechanistically, VPA suppresses neuronal hyperexcitability through GABAergic enhancement and ion channel modulation, while its role as a histone deacetylase (HDAC) inhibitor facilitates systemic epigenetic regulation and transcriptional control. This review synthesizes current evidence on VPA's pleiotropic molecular actions, evaluating its dual role as a pharmacological agent and molecular modulator within the framework of precision medicine. However, VPA's therapeutic promise is tempered by significant adverse effects, including hepatotoxicity, thrombocytopenia, and potent teratogenicity. Gestational exposure is of particular concern, where transplacental transfer and interference with fetal neurogenesis lead to long-term neurodevelopmental disruptions. This evolving profile necessitates a nuanced risk-benefit analysis and underscores the need for vigilant clinical oversight and pharmacogenomic stratification in vulnerable populations.