Graphical Abstract.

APX3330 treatment in the animal model of chronic spontaneous colitis inhibits APE1/Ref-1 redox signalling, mitochondrial superoxide production, oxidative DNA damage and translocation of HMGB1 from the nucleus into cytoplasm and extracellularly. Extracellular HMGB1 stimulates immune cells to release cytokines and chemokines. APX3330 treatment alleviates the immune response. Suppressing APE1/Ref-1 redox activity enhances its endonuclease repair activity. These mechanisms alleviate damage to the enteric nervous system and GI dysfunction leading to improved clinical signs associated with chronic colitis.