"Following oral intake, Diquat directly targets intestinal epithelial cells, where it generates excessive ROS through redox cycling. This leads to the downregulation of tight junction proteins such as ZO-1, occludin, and claudin-1, thereby significantly increasing intestinal permeability (Jin et al., 2021; Cao et al., 2019). The resulting barrier dysfunction facilitates the translocation of endotoxins and unmetabolized Diquat molecules from the gut lumen into the systemic circulation, subsequently triggering a systemic inflammatory response via activation of the TLR4/NF-κB signaling pathway (Cui et al., 2023; Huang et al., 2024; Liu et al., 2021; Zhan et al., 2025). In this process, the gut microbiota plays a pivotal “amplifier” role: Diquat inhibits the proliferation of beneficial bacteria such as Lactobacillus, while promoting the enrichment of potentially pathogenic taxa such as Actinobacteria and Ruminococcaceae, leading to a reduction in key microbial metabolites including indole-3-methanol, 5-hydroxyindole-3-acetic acid, and uridine (Fu et al., 2021). These small molecules are normally involved in maintaining intestinal barrier integrity and immune tolerance through activation of the aryl hydrocarbon receptor (AhR). Their depletion exacerbates mucosal damage and inflammatory cascades (Kahalehili et al., 2020; Dang et al., 2023). This resulting cycle of “oxidative stress–microbial dysbiosis–inflammatory amplification” may serve as a key driving force in the development of MODS."

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1562182/full