Glyphosate-triggered hepatocyte ferroptosis via suppressing Nrf2/GSH/GPX4 axis exacerbates hepatotoxicity

Abstract

Glyphosate (GLY) exposure has been reported to damage organs in animals, in particular the liver, due to increased reactive oxygen species (ROS). Ferroptosis is defined as a new type of cell death that is characterized by the increase of ROS. The purpose of this study was to elucidate whether the relationship between ferroptosis and GLY-induced hepatotoxicity is of significance to enlarge the knowledge about GLY toxicity and consequences for human and animal health. To this end, in this study, we investigated the role of ferroptosis in GLY-induced hepatotoxicity both in vivo and in vitro. The results showed that GLY exposure triggered ferroptosis in L02 cells, but pretreatment with ferroptosis inhibitor ferrostatin (Fer-1) rescued ferroptosis-induced injury, thereby indicating that ferroptosis plays a key role in GLY-induced hepatotoxicity. Moreover, N-acetylcysteine, a glutathione (GSH) synthesis precursor, reversed GLY-triggered ferroptosis damage, thus indicating that GSH exhaustion may be a prerequisite for GLY-triggered hepatotoxicity. Mechanistically, GLY inhibited GSH biosynthesis via blocking the phosphorylation and nuclear translocation of Nrf2, which resulted in GSH depletion-induced hepatocyte ferroptosis. In a mouse model, GLY exposure triggered ferroptosis-induced liver damage, which can be rescued by pretreatment with Fer-1 or tBHQ (a specific agonist of Nrf2). To our knowledge, this is the first study to reveal that GLY-triggered hepatocyte ferroptosis via suppressing Nrf2/GSH/GPX4 axis exacerbates hepatotoxicity, which expands our knowledge about GLY toxicity in animal and human health.