Valproic acid-induced oxidative stress: Systematic review, meta-analysis and network pharmacology highlights disruption in antioxidant pathways in rodents

Valproic acid (VPA) is a widely used antiepileptic drug, but its effects on oxidative stress in rodent models have not been systematically reviewed. This meta-analysis aimed to evaluate the impact of VPA on oxidative stress markers in rodents and explore underlying mechanisms through network pharmacology. A systematic search of PubMed, Web of Science, and PsycINFO (2010-2024) was conducted, following PRISMA and CAMARADES guidelines. Forty-two studies involving 639 rodents were included. Meta-analysis and meta-regression were performed using SPSS and R, and network pharmacology identified key pathways. From 1802 studies, 42 met the criteria, involving 639 rodents. VPA treatment was associated with a significant increase in malondialdehyde (MDA) levels (SMD = 30.45, 95 % CI: 17.64-43.25, P < 0.001) and a decrease in clinically relevant biomarkers, such as superoxide dismutase (SOD) (SMD = -13.22, 95 % CI: -19.39--7.04, P < 0.001), glutathione (GSH) (SMD = -16.97, 95 % CI: -28.13--5.82, P < 0.001), catalase (CAT) (SMD = -9.24, 95 % CI: -13.85--4.62, P < 0.001), glutathione S-transferases (GST) (SMD = -8.82, 95 % CI: -17.40--0.24, P = 0.040), and glutathione peroxidase (GPx) (SMD = -36.05, 95 % CI: -60.72--11.37, P < 0.001). Meta-regression analysis suggested that dosing periods and doses significantly impacted oxidative stress markers. Network pharmacology analysis identified 33 key targets and significant pathways, including MAPK signaling, Toll-like receptor signaling, and TNF signaling. VPA induces oxidative stress in rodent models by increasing MDA and reducing antioxidants, suggesting potential oxidative stress-related side effects in patients.