Zhang Yi-Ming, Zhang Zhi-Gang
Gastroenterology Clinic Ward, First Department of The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China.
General Practice Clinic Ward, Second Department of The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China.
World J Psychiatry. 2025 Sep 19;15(9):108382. doi: 10.5498/wjp.v15.i9.108382.
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.
多种肝脏疾病及其相关并发症，尤其是肝性脑病，影响着全球数百万人，包括非酒精性脂肪性肝病、酒精性肝损伤、病毒性肝炎、肝纤维化、肝硬化和肝细胞癌等疾病。其潜在的致病机制是多因素的，包括氧化应激、炎症级联反应、线粒体损伤和免疫稳态紊乱。肝性脑病患者会出现认知障碍、情绪紊乱和精神运动功能障碍，通过氧化应激、神经炎症和神经递质失衡等机制显著降低生活质量。核因子红细胞2相关因子2（Nrf2）/血红素加氧酶-1（HO-1）信号通路在这些情况下起着关键的抗氧化防御作用。Nrf2调节保护酶的表达，而HO-1则通过血红素降解产物发挥抗炎、抗凋亡和抗纤维化作用。天然草药单体作为Nrf2激活剂具有低毒性、多靶点作用和广泛传统应用的优势。各种草药单体对不同的肝脏疾病具有特定作用：在脂肪肝中，黄芩苷可减轻脂质积累和炎症；在酒精性肝病中，姜黄素可增强Nrf2活性，减少氧化损伤；在药物性肝损伤中，二氢杨梅素可减轻氧化应激；在病毒性肝炎中，穿心莲内酯可抑制丙型肝炎病毒复制；在肝纤维化中，多种化合物可抑制星状细胞活化。这些天然化合物通过调节Nrf2/HO-1途径同时减轻肝功能障碍和神经精神症状，不过临床应用仍面临生物利用度低等挑战，需要进一步研究。
