Silibinin meglumine ameliorates hepatic encephalopathy via inhibiting UCP2-mediated oxidative stress and mitochondrial dysfunction

Hepatic encephalopathy (HE) is a serious clinical challenge lacking effective therapies. Silybin, one major active component of milk thistle, is a natural product recognized for its protective properties against diverse hepatic diseases and neurodegenerative conditions. Silibinin meglumine (SM) is a meglumine salt of silybin and is extensively utilized in the treatment of liver diseases. However, the potential effects and underlying mechanisms of SM on HE are still not completely understood. In the present study, our findings demonstrated that SM lowered serum ammonia and improved liver function indicators such as alanine transaminase, aspartate transaminase, and total bilirubin in thioacetamide (TAA)-induced HE mice. SM also reduced inflammatory cytokines, including tumor necrosis factor and interleukin-6, in both plasma and brain tissue, decreased oxidative stress markers malondialdehyde and increased glutathione levels. Furthermore, the subsequent molecular docking, cellular thermal shift assay, drug affinity responsive target stability assay and microscale thermophoresis assay indicated that uncoupling protein 2 (UCP2) might be a potential target for SM in ameliorating HE. Notably, SM downregulated UCP2 expression in liver tissue, and alleviated oxidative stress and mitochondrial dysfunction via the UCP2/PINK1/Drp1/MFN2/LC3B pathway. Additionally, after the administration of a UCP2 inhibitor, the antioxidant effect of SM was partially attenuated; however, there was no statistically significant reduction in the enzyme activities of ALT and AST. In summary, this study demonstrated that targeting UCP2 with SM could enhance mitochondrial function in the liver and inhibit mitophagy, thereby potentially ameliorating TAA-induced HE. These findings indicate that SM may represent a promising therapeutic approach for TAA-induced HE.