Single-cell analysis of diquat-induced oxidative stress and its impact on organ-specific toxicity

Diquat (DQ) is a commonly used herbicide, and its improper use can lead to multi-organ damage. The characteristics of multi-organ damage induced by DQ are not yet well understood. In this study, we conducted single-cell/single-nucleus RNA sequencing (scRNA-seq/snRNA-seq) on the lungs, liver, and kidneys of mice at consecutive time points (10 hours, 20 hours, and 36 hours) after DQ poisoning, as well as in a control group. In a multi-organ single-cell atlas comprising over 270,000 cells from mice, we found that DQ induces an oxidative stress microenvironment in endothelial and parenchymal cells, primarily characterized by activation of the oxidative phosphorylation pathway and an enhanced inflammatory response. This oxidative stress microenvironment prompted regulatory cell death in parenchymal and immune cells, releasing inflammatory factors and further exacerbating the oxidative environment. Additionally, metabolic reprogramming occurred in both parenchymal and immune cells under oxidative stress, leading to alterations in energy metabolism, reduced hepatic detoxification capabilities, and changes in the activation modes of immune cells, thereby intensifying tissue damage. Notably, no significant fibrosis was observed in the tissue damage caused by DQ, underscoring the importance of early intervention. Overall, using a mouse model, this study revealed the central role of the DQ-induced oxidative stress microenvironment in multi-organ damage and enhanced our understanding of the pathophysiology and complex molecular mechanisms underlying DQ-induced multi-organ injury.