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Advanced glycation end products (AGEs) excessive accumulation in the body either by exogenous intake or endogenous formation makes individuals prone to oxidative stress and inflammation damage. In this study, DCFH-DA fluorescence test and qPCR experiment were carried out to study the effect of some dietary flavonoids on AGEs induced toxicity. Among four tested flavonoids, it was found that hesperetin could significantly inhibit both AGEs-induced ROS production and gene expressions of TNF-α, IL-1β, IL-6, MCP-1, COX-2 and iNOS. High-throughput transcriptome analysis showed that the protective effect of hesperetin against AGEs-induced toxicity might be attributed to inhibit the activation of MAPK, JAK, NF-κB-related pathways. Furthermore, gene set enrichment analysis was performed using the MSigDB database and twenty-three key genes related were screened. This study might provide new ideas for the prevention of AGEs-related diseases and lay a theoretical foundation for the application of dietary flavonoids.