Ganfule capsule alleviates AFB1-induced toxic liver injury via inhibiting oxidative stress, inflammatory response, and apoptosis

Abstract

Aflatoxins, particularly aflatoxin B1 (AFB1), are widely present in the environment and pose a significant risk to food safety. However, no specific drugs are available for AFB1-induced toxic liver injury. Ganfule (GFL) is a traditional Chinese medicine (TCM) formula approved in China for the adjunctive treatment of advanced liver cancer. Nonetheless, its effects on AFB1-induced toxic liver injury remain unclear. In this study, cell and animal experiments have shown that GFL activates the Kelch like ECH associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant pathway in liver or hepatocytes. This leads to an increase in superoxide dismutase (SOD) activity and glutathione (GSH) level, a decrease in reactive oxygen species (ROS) and malondialdehyde (MDA) levels, and inhibition of AFB1-induced oxidative stress. GFL also reduces the levels of inflammatory factors and fibrosis-related genes by inhibiting the interleukin 6 (IL6)/signal transducer and activator of transcription 3 (STAT3) pathway. Furthermore, GFL suppresses the expression of pro-apoptotic genes while enhancing the expression of anti-apoptotic genes, effectively preventing AFB1-induced hepatocyte apoptosis and improving liver function in mice. Network pharmacology predictions, and transcriptome sequencing confirms that GFL exerts its therapeutic effect through the regulation of the aforementioned pathways. Molecular docking analysis, molecular dynamics simulation, and in vitro experiments suggest that quercetin (QCT) mediates its effects through specifically binding to IL6 and STAT3, resulting in the subsequent inhibition of the IL6/STAT3 signaling pathway. This study elucidates the pharmacological mechanism of GFL in treating AFB1-induced toxic liver injury, providing theoretical evidence for its clinical application.