The Potential of Targeting APE1/Ref-1 as a Therapeutic Intervention for Duchenne Muscular Dystrophy

Significance: Inflammation and oxidative stress play crucial roles in the development and progression of skeletal muscle diseases. This review aims to examine the existing evidence regarding the involvement and inhibition of APE1/Ref-1 (apurinic/apyrimidinic endonuclease 1/redox factor 1) in diseases, then extrapolate this evidence to the context of skeletal muscle and discuss the potential beneficial effects of APE1/Ref-1 inhibition in ameliorating myopathy with a particular focus on dystrophic pathology. Critical Issues: Currently, therapeutic interventions targeting pathways, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and nuclear factor erythroid 2-related factor 2 (NRF2), have shown limited efficacy in both clinical and preclinical settings. Thus, there is a need for a more comprehensive treatment approach. Recent Advances: APE1/Ref-1 is a multifunctional protein that was initially identified as being involved in DNA repair. However, newer research has revealed its additional role as a redox-sensitive regulator of transcription factors, including NF-κB and NRF2. Numerous studies have reported increased expression of APE1/Ref-1 in various disorders and have demonstrated the beneficial effects of inhibiting its redox function using the small molecular inhibitor, APX3330. Although these pathways are similarly dysregulated in neuromuscular disorders, the specific role of APE1/Ref-1 in skeletal muscle remains unclear, with only a limited number of studies noting its presence in this tissue. Future Directions: Further studies investigating the role of APE1/Ref-1 in skeletal muscle and identifying whether APE1/Ref-1 is up- or downregulated in dystrophic skeletal muscle would be required to determine whether upregulating or inhibiting the redox function of APE1/Ref-1 will alleviate chronic inflammation and heightened oxidative stress. Antioxid. Redox Signal. 00, 000-000.