APE1/Ref-1 as a Therapeutic Target for Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammation of the gastrointestinal tract. The prevalence of IBD is increasing with approximately 4.9 million cases reported worldwide. Current therapies are limited due to the severity of side effects and long-term toxicity, therefore, the development of novel IBD treatments is necessitated. Recent findings support apurinic/apyrimidinic endonuclease 1/reduction-oxidation factor 1 (APE1/Ref-1) as a target in many pathological conditions, including inflammatory diseases, where APE1/Ref-1 regulation of crucial transcription factors impacts significant pathways. Thus, a potential target for a novel IBD therapy is the redox activity of the multifunctional protein APE1/Ref-1. This review elaborates on the status of conventional IBD treatments, the role of an APE1/Ref-1 in intestinal inflammation, and the potential of a small molecule inhibitor of APE1/Ref-1 redox activity to modulate inflammation, oxidative stress response, and enteric neuronal damage in IBD.

Keywords: apurinic/apyrimidinic endonuclease 1/reduction-oxidation factor 1 (APE1/Ref-1); inflammation; inflammatory bowel disease (IBD); oxidative stress; redox signaling.

Figure 1

APE1/Ref-1 role in inflammatory bowel disease and the potential of redox signaling inhibition. The activation of transcription factors through the redox function of APE1 is implicated in the promotion of inflammation in inflammatory bowel disease. Furthermore, the subsequent activation of downstream mediators directly affects the inflammatory responses. By inhibiting the redox signaling pathway using APX compounds, the excessive production of pro-inflammatory cytokines, chemokines, reactive oxygen species (ROS), and neuronal damage can be reduced, leading to the alleviation of inflammation and gastrointestinal functions. Additionally, the repair function of APE1 plays a crucial role in mending the DNA or RNA lesions caused by inflammation and oxidative stress. In summary, the utilization of APX compounds can effectively diminish inflammatory markers, ROS levels, and enteric neuropathy, while also enhancing the DNA repair function, thereby presenting a novel therapeutic opportunity for IBD (created with BioRender.com (accessed on 30 September 2023)). Abbreviations: TFs: transcription factors; IL: interleukin; TNF-α: tumor necrosis factor-alpha; ROS: reactive oxygen species; STAT3: signal transducer and activator of transcription 3; NFκB: nuclear factor kappa-light chain enhancer of activated B cells; AP-1: activator protein 1; HIF1α: hypoxia-inducible factor 1 subunit alpha; redox: reduction-oxidation; LPS: lipopolysaccharide; TLR4: toll-like receptor 4; DNA: deoxyribonucleic acid.