SGK1 Inhibition Improved Mitochondrial Dysfunction and Astrocyte Senescence in Hepatic Encephalopathy via...

Astrocyte senescence plays an essential role in CNS disorders. However, the understanding of astrocyte senescence and its regulatory targets in hepatic encephalopathy (HE) is limited. SGK1 was reported to regulate astrocyte senescence. Therefore, the current study aimed to investigate the role of SGK1 and astrocyte senescence in HE. The rat model of HE was established by common bile duct ligation. Adeno-associated virus (AAV) was used for astrocyte-specific knockdown of SGK1. The rats were also evaluated with behavioral tests. Primary rat astrocytes were used for in vitro validation. RNA-sequencing was used to further investigate the underlying mechanisms. SGK1 was significantly upregulated in HE, especially in astrocytes. Cellular senescence was enriched in the expression profiles of the brain from HE patients, when senescence-associated secretory phenotype (SASP) and mitochondrial dysfunction were also activated in astrocytes from the rat model of HE. Knockdown of astrocyte SGK1 ameliorated HE by alleviating cellular senescence and mitochondrial dysfunction, when the underlying mechanisms were tightly associated with interferon response. Alleviated astrocyte SASP by SGK1 knockdown further protected against neuroinflammation by suppressing microglia activation and pro-inflammatory polarization. The effects of SGK1 on astrocyte senescence were mediated by the IL-6/JAK2/STAT3 signaling pathway. SGK1 inhibition improved HE by ameliorating astrocyte senescence and mitochondrial dysfunction. SGK1 and the downstream IL-6/JAK2/STAT3 signaling pathway might be novel therapeutic targets for the treatment of HE.