Atrazine increases hepatic inflammation and injury via endoplasmic reticulum (ER) stress mediated excessive formation of mitochondria-associated membranes (MAMs) and activation of the cGAS-STING pathway.

Despite its widespread application as a triazine herbicide, atrazine (ATR) poses significant health threats, with the mechanisms underlying its induction of hepatic inflammation still not fully elucidated. Our research delineates a mechanistic cascade in which ATR exposure is associated with endoplasmic reticulum (ER) stress induction, which in turn stimulates the excessive generation of mitochondria-associated membranes (MAMs). This event is associated with mitochondrial calcium inundation, augmented generation of mitochondrial reactive oxygen species (mtROS), and the cytosolic translocation of mitochondrial DNA (mtDNA). Subsequently, cytosolic mtDNA may operates as a damage-associated molecular pattern (DAMP), which engages the cGAS-STING pathway and nucleates NLRP3 inflammasome assembly, ultimately provoking a severe hepatic inflammatory response. These findings were consistently validated through both in vitro experiments and mouse models. Furthermore, inhibition of ER stress with 4-PBA significantly reduced MAMs over-assembly and alleviated mitochondrial dysfunction. Scavenging mitochondrial ROS with MitoQ also effectively attenuated downstream inflammatory activation. Overall, this study identifies a novel mechanistic pathway of ATR-induced hepatotoxicity: ER stress-MAMs-mitochondrial damage-mtDNA release-cGAS-STING-NLRP3 inflammation, providing new insights into the toxicology of environmental chemicals and suggesting potential therapeutic strategies for pollutant-induced liver injury.