Myricetin and 2-amino-3-methyl-3H-imidazole [4, 5-F] quinoline triggers liver injury by regulating gut microbiota and liver metabolism.

2-Amino-3-methyl-3H-imidazole[4,5-f]quinoline (IQ), a typical nitrogen-containing oxidized organic pollutant, is predominantly ingested through thermally processed foods. Although existing toxicological research has mainly focused on the direct health impacts of IQ itself, the modulatory effects of dietary components on its toxicity characteristics remain mostly unexplored. Intriguingly, our previous in vitro study showed that myricetin (MY), a naturally occurring flavonoid renowed for its well-documented anti-inflammatory and antioxidant properties, unexpectedly aggravated IQ-induced cytotoxicity at subtoxic exposure levels, challenging the conventional idea of flavonoid-mediated cytoprotection. In this study, we inspected the effect and underlying mechanism of MY on liver injury induced by non-toxic low dose IQ in mice. Results indicated that co-administration of MY (70 mg/kg bw) and IQ (7 mg/kg bw) led to liver damage, as confirmed by histological analysis and serum biochemical markers. Meanwhile, non-targeted metabolomic analysis revealed that co-treatment of MY and IQ disrupted liver metabolic balance, resulting in notable changes in inflammation-related metabolites and metabolic pathways. Furthermore, co-administration of IQ and MY also activated the NF-κB/MAPK pathway and promoted the expression of the NLRP3 inflammasome, ultimately resulting in liver damage. Moreover, 16S rRNA sequencing data demonstrated that MY exacerbated IQ-induced intestinal microbiota dysregulation. In conclusion, our study highlights that MY enhances the liver toxicity of non-toxic IQ in vivo, providing valuable theoretical insights into the toxicological properties of the oxidized nitrogen-containing organic pollutants IQ.