Targeting the DNA repair enzymes MTH1 and OGG1 as a novel approach to treat inflammatory diseases.

Autoimmune diseases and acute inflammation like sepsis cause significant morbidity and disability globally, and new targeted therapies are urgently needed. DNA repair and reactive oxygen species (ROS) pathways have long been investigated as targets for cancer treatment, but their role in immunological research has been limited. In this MiniReview, we discuss the DNA repair enzymes MTH1 and OGG1 as targets to treat both T cell-driven diseases and acute inflammation. The MiniReview is based on a PhD thesis where both enzymes were investigated with cell and animal models. For MTH1, we found that its inhibition selectively kills activated T cells without being toxic to resting cells or other tissues. MTH1 inhibition also had an alleviating role in disease models of psoriasis and multiple sclerosis. We further identified a novel MTH1low ROSlow phenotype among activated T cells. Regarding OGG1, we demonstrated a mechanism of action of the OGG1 inhibitor TH5487, which prevents the assembly of pro-inflammatory transcription factors and mitigates acute airway infection in mouse models of pneumonia. Hence, we propose both enzymes to be promising novel targets to treat inflammation and suggest that redox and DNA repair pathways could be useful targets for future immunomodulating therapies.