Dihydroartemisinin beneficially regulates splenic immune cell heterogeneity through the SOD3-JNK-AP-1 axis

The immunomodulatory potential of dihydroartemisinin (DHA) has recently been highlighted; however, the potential mechanism remains to be clarified. Single-cell RNA sequencing was explored in combination with cellular and biochemical approaches to elucidate the immunomodulatory mechanisms of DHA. In this study, we found that DHA induced both spleen enlargement and rearrangement of splenic immune cell subsets in mice. It was revealed that DHA promoted the reversible expansion of effective regulatory T cells and interferon-γ⁺ cytotoxic CD8⁺ T cells in the spleen via induction of superoxide dismutase 3 (SOD3) expression and increased phosphorylation of c-Jun N-terminal kinases (JNK) and its downstream activator protein 1 (AP-1) transcription factors. Further, SOD3 knockout mice were resistant to the regulatory effect of DHA. Thus, DHA, through the activation of the SOD3-JNK-AP-1 axis, beneficially regulated immune cell heterogeneity and splenic immune cell homeostasis to treat autoimmune diseases.