ORIGINAL ABSTRACT

Glyphosate, the most widely used herbicide worldwide, is now ubiquitous in the environment, posing a growing threat to human health. While accumulating evidence has linked glyphosate exposure to liver injury, the underlying mechanisms remain unclear. In this study, based on data from NHANES 2013-2018, we identified significant associations between glyphosate exposure and abnormal liver function parameters in the general US population. A glyphosate-exposed mouse model was further established, and the results showed that hepatic accumulation of glyphosate induced direct histopathological damage and increased serum AST, ALT, and ALP levels in mice. Combined network toxicology and gene set analyses revealed that glyphosate activated liver macrophages, upregulating genes related to lipid metabolism, inflammation, and pyroptosis. The activation of the pyroptosis pathway was further confirmed by Western blot analysis of NLRP3 inflammasome-associated proteins. Mechanistically, glyphosate disrupted mitochondrial membranes and compromised mitochondrial function, leading to the release of mtDNA, which subsequently activated the cGAS-STING pathway in mouse livers and RAW264.7 macrophages. Moreover, glyphosate-induced NLRP3 activation in RAW264.7 cells was attenuated by the cGAS inhibitor. These findings provide a novel mechanistic insight into glyphosate-induced hepatotoxicity and reinforce the growing concern over its association with liver injury in humans.