Targeting mitochondrial ROS in the liver-brain axis attenuates inflammation and oxidative stress in covert hepatic...

Covert hepatic encephalopathy (CHE) is a debilitating complication of chronic liver disease, in which hyperammonemia and oxidative stress play central pathogenic roles. While mitochondria-targeted antioxidants show promise in mitigating multi-organ injury, their efficacy in CHE remains insufficiently studied. To address this gap, this study analyzed clinical samples and observed significant dysregulation of peripheral oxidative stress markers in cirrhotic patients with hyperammonemia. Subsequently, in vitro experiments demonstrated that the mitochondria-targeted antioxidant MitoQ effectively attenuated ammonia-induced mitochondrial reactive oxygen species overproduction, loss of membrane potential, and impaired ATP synthesis in neuronal cells. In a bile duct ligation-induced mouse model of CHE, MitoQ administration not only alleviated hepatic injury and fibrosis but also concurrently reduced oxidative stress and inflammatory cytokine levels in the liver, blood, and brain. These changes were accompanied by marked improvements in motor coordination and systemic energy metabolism stability. Collectively, our findings indicate that MitoQ exerts multi-organ protective effects by targeting mitochondrial ROS along the liver-brain axis, restoring redox homeostasis and suppressing inflammation, thereby proposing a novel integrated therapeutic strategy for CHE. This study contributes to the mechanistic understanding of liver-brain crosstalk in HE and offers preliminary preclinical evidence that suggests a potential role for mitochondrial-targeted antioxidants in the management of hepatic encephalopathy, which also require independent validation in larger cohorts.