Arctigenin Attenuates Hepatic Ischemia/Reperfusion Injury by Enhancing NRF2-GST/GPX4 Antioxidant Response
Year: 2026
Type: article
Abstract: Hepatic ischemia/reperfusion injury (IRI) remains a major cause of graft dysfunction and postoperative liver failure, and no specific pharmacological therapy is available. Oxidative stress plays a key role in hepatic IRI, making arctigenin (AG), a compound with antioxidant and anti-inflammatory activities, a potential therapeutic candidate. We evaluated AG using a 70% hepatic ischemia/reperfusion model in male C57BL/6 mice and cellular injury models induced by hypoxia/reoxygenation (H/R) or H2O2 exposure in AML12 cells. AG dose-dependently attenuated hepatic injury, reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, and decreased hepatic necrosis. AG also reduced inflammatory macrophage abundance and pro-inflammatory cytokine expression in the liver after IRI. In AML12 cells, AG improved viability and reduced ROS accumulation and lipid peroxidation. Transcriptomic analysis identified glutathione metabolism, glutathione transferase activity, and cellular detoxification as major AG-responsive processes. AG promoted nuclear accumulation of nuclear factor erythroid 2-related factor 2 (NRF2), increased the expression of multiple glutathione S-transferases (GSTs) and glutathione peroxidase 4 (GPX4), and enhanced GST and GSH-Px activities. Pharmacological inhibition of NRF2, GPX4, or GSTs attenuated AG-mediated cytoprotection. NRF2 knockdown also weakened AG-associated improvements in cell viability, apoptosis, ROS levels, and antioxidant enzyme activities after H/R. In mice, ML385 attenuated AG-associated antioxidant responses and hepatoprotection. These findings support a role for NRF2 in AG-mediated protection and implicate GST- and GPX4-associated antioxidant defenses in its effects against hepatic IRI.
Institutions: Xuzhou University of Technology, Jiangnan University
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,499
OpenAlex ID: W7225777453