Zhang YM, Zhang ZG. Modulating nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 in liver-brain axis disorders. World J Psychiatry 2025; 15(9): 108382 [DOI: 10.5498/wjp.v15.i9.108382]
Corresponding Author of This Article
Zhi-Gang Zhang, MD, Doctor, General Practice Clinic Ward, Second Department of The First Affiliated Hospital of Dalian Medical University, No. 222 Zhongshan Road, Dalian 116011, Liaoning Province, China. m18098875906@163.com
Research Domain of This Article
Psychology, Clinical
Article-Type of This Article
Review
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Psychiatry. Sep 19, 2025; 15(9): 108382 Published online Sep 19, 2025. doi: 10.5498/wjp.v15.i9.108382
Modulating nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 in liver-brain axis disorders
Yi-Ming Zhang, Zhi-Gang Zhang
Yi-Ming Zhang, Gastroenterology Clinic Ward, First Department of The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
Zhi-Gang Zhang, General Practice Clinic Ward, Second Department of The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
Author contributions: Zhang YM conceived and designed the study, performed the statistical analysis, and wrote the manuscript; Zhang ZG collected and processed the data, conducted literature research, and critically revised the manuscript for important intellectual content; Both authors reviewed and approved the final version of the manuscript.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Zhi-Gang Zhang, MD, Doctor, General Practice Clinic Ward, Second Department of The First Affiliated Hospital of Dalian Medical University, No. 222 Zhongshan Road, Dalian 116011, Liaoning Province, China. m18098875906@163.com
Received: May 9, 2025 Revised: June 12, 2025 Accepted: July 17, 2025 Published online: September 19, 2025 Processing time: 109 Days and 2.7 Hours
Abstract
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.
Core Tip: This study explores the critical role of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway in mitigating liver-brain axis dysfunction. By investigating oxidative stress, inflammatory markers, and neurocognitive outcomes, we demonstrate that activating Nrf2/HO-1 can alleviate liver-induced neural deficits. Using both in vitro and in vivo models, our findings reveal that Nrf2/HO-1 modulation significantly reduces neuroinflammation and oxidative damage, offering a potential therapeutic strategy for managing hepatic encephalopathy. This concise analysis underscores the importance of targeting Nrf2/HO-1 to maintain neural integrity, reduce systemic inflammation, and improve cognitive functions in patients with liver-related neurological complications.
