Targeting the p38MAPK/STAT3/NF-κB65 pathway modulates the hepatoprotective effect of pentoxifylline against sodium valproate-induced liver injury in rats; A study based on integrating network pharmacology and experiment validation

Abstract

Sodium valproate (SVP) is frequently utilized in the treatment of epilepsy. Extended administration of SVP elevates the likelihood of hepatotoxicity. Pentoxifylline (PTX) functions as a nonselective phosphodiesterase inhibitor and is commonly utilized in the treatment of vascular conditions, exhibiting extensive antioxidant and anti-inflammatory properties. This research examined PTX's protective role in mitigating SVP-induced liver injury, clarifying the potential molecular mechanisms involved. SVP and PTX intersection targets were identified through network pharmacology. In addition, we conducted an in vivo experiment utilizing the SVP-induced liver injury model. Eighteen adult male rats were allocated to three groups, with the control group receiving oral normal saline. The SVP group was administered SVP (dissolved in normal saline) daily for 2 weeks. The PTX + SVP group was administered SVP in conjunction with PTX daily for two weeks. PTX hepatoprotective effect against SVP could include apoptosis, anti-inflammatory mechanisms, and various signaling pathways, such as NF-κB, STAT3, and MAPK, as indicated by the KEGG and GO enrichment analysis of the 272 common targets. We identified BCL2, IL6, and TNF as potential hub targets of PTX for liver injury treatment based on the construction of the PPI network. In vivo experiments demonstrated that PTX hindered MAPK P38/STAT3/NF-κB-related pathways' activation, diminished oxidative stress, apoptosis, and inflammatory response, and substantially ameliorated SVP-induced liver injury. The network pharmacology study concluded that the MAPK P38/STAT3/NF-κB pathway plays a role in PTX protective effect against SVP-induced liver injuries, as demonstrated by the in vivo experiment results.