Rifaximin protects SH-SY5Y neuronal cells from iron overload-induced cytotoxicity via inhibiting STAT3/NF-κB signaling

Abstract

Acute or chronic liver disease-caused liver failure is the cause of hepatic encephalopathy (HE), characterized by neuropsychiatric manifestations. Liver diseases potentially lead to peripheral iron metabolism dysfunction and surges of iron concentration in the brain, contributing to the pathophysiological process of degenerative disorders of the central nervous system. In this study, the mechanism of rifaximin treating HE was investigated. Ferric ammonium citrate (FAC)-induced iron overload significantly reduced the proliferation and boosted the apoptosis in SH-SY5Y cells through increasing reactive oxygen species (ROS) levels and inducing iron metabolism disorder. Rifaximin treatment could rectify the FAC-induced iron overload and lipopolysaccharide (LPS)-induced iron deposition, therefore, effectively protecting SH-SY5Y cells from ROS-induced cell injury and apoptosis. Signal transducer and activator of transcription 3 (STAT3)/nuclear factor-kappa B (NF-κB) signaling is involved in the protective function of rifaximin against LPS-induced iron deposition. The therapeutic effect of rifaximin on HE associated with acute hepatic failure in mouse model was ascertained. In conclusion, Rifaximin could effectively protect SH-SY5Y cells against injury caused by iron overload through the rectification of the iron metabolism disorder via the STAT3/NF-κB signaling pathway.

Keywords: STAT3/NF-κB signaling pathway; hepatic encephalopathy (HE); lipopolysaccharide (LPS); reactive oxygen species (ROS); rifaximin.