Modulating nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 in liver-brain axis disorders

A broad spectrum of liver disorders and their associated complications most notably hepatic encephalopathy impact millions of individuals worldwide, including conditions such as non-alcoholic fatty liver disease, alcoholic liver injury, viral hepatitis, hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. The underlying pathogenic mechanisms are multifactorial, encompassing oxidative stress, inflammatory cascades, mitochondrial impairment, and disturbances in immune homeostasis. Hepatic encephalopathy patients experience cognitive impairment, mood disturbances, and psychomotor dysfunction, significantly reducing quality of life through mechanisms including oxidative stress, neuroinflammation, and neurotransmitter imbalances. The nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway serves as a critical antioxidative defense mechanism in these conditions. Nrf2 regulates the expression of protective enzymes, while HO-1 exerts anti-inflammatory, anti-apoptotic, and antifibrotic effects through heme degradation products. Natural herbal monomers as Nrf2 activators offer advantages of low toxicity, multi-target actions, and extensive traditional use. Various herbal monomers demonstrate specific effects against different liver diseases: In fatty liver, baicalin alleviates lipid accumulation and inflammation; In alcoholic liver disease, curcumin enhances Nrf2 activity reducing oxidative damage; In drug-induced liver injury, dihydromyricetin mitigates oxidative stress; In viral hepatitis, andrographolide inhibits hepatitis C virus replication; In liver fibrosis, multiple compounds inhibit stellate cell activation. These natural compounds simultaneously alleviate hepatic dysfunction and neuropsychiatric symptoms by modulating the Nrf2/HO-1 pathway, though clinical application still faces challenges such as low bioavailability, requiring further research.