Mechanism of GCN2/eIF2α signaling pathway in MC-LR-induced hepatocyte oxidative damage and alpha-lipoic acid intervention.

Prior research indicates that α-lipoic acid (α-LA) confers protection against the hepatotoxic effects of microcystin-LR (MC-LR), although the precise mechanisms remain to be fully defined. This investigation aims to elucidate how the reactive oxygen species (ROS)-mediated GCN2/eIF2α pathway enables α-LA to mitigate oxidative damage in hepatocytes caused by MC-LR, thus providing a robust scientific foundation for elucidating the mechanisms of MC-LR-induced cellular damage and identifying novel preventive and therapeutic approaches. For this purpose, human normal hepatocytes (L02 cells) and mouse normal hepatocytes (AML12 cells) were categorized into ten experimental groups: a blank control group, a 1 μM MC-LR exposure group, a 50 μg/mL α-LA group, combined MC-LR and α-LA groups, an siGCN2 group, a GCN2 inhibitor (GCN2iB) group, and groups treated with 1 μM MC-LR in conjunction with siGCN2 or GCN2iB. The investigation revealed that MC-LR diminishes SOD activity, elevates MDA levels, reduces mitochondrial membrane potential, and stimulates ROS generation, culminating in oxidative cellular damage. MC-LR activates the GCN2/eIF2α pathway by promoting ROS, resulting in oxidative damage to cells. Furthermore, application of inhibitors or silencing of GCN2 activity can reduce ROS generation, thereby attenuating MC-LR-induced oxidative damage in hepatocytes. α-LA pretreatment enhances the antioxidant capacity of AML12 cells and L02 cells and alleviates MC-LR-induced oxidative stress (OS). It is suggested that α-LA can protect AML12 cells and L02 cells from oxidative damage caused by MC-LR to a certain extent. α-LA can alleviate MC-LR-induced oxidative damage in AML12 and L02 cells to a certain extent by inhibiting the GCN2/eIF2α pathway.