Lalunio Hannah, Stupka Nicole, Goodman Craig A, Hayes Alan
Department of Medicine-Western Health, Melbourne Medical School, The University of Melbourne, Parkville, Australia.
Australian Institute for Musculoskeletal Science (AIMSS), Victoria University, St. Albans, Australia.
Antioxid Redox Signal. 2025 May;42(13-15):641-654. doi: 10.1089/ars.2024.0620. Epub 2024 Dec 27.
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. 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. 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. 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. 42, 641-654.
炎症和氧化应激在骨骼肌疾病的发生和发展中起着关键作用。本综述旨在研究关于脱嘌呤/脱嘧啶内切核酸酶1/氧化还原因子1（APE1/Ref-1）参与疾病及对其抑制作用的现有证据，然后将此证据推广到骨骼肌背景下，并讨论抑制APE1/Ref-1在改善肌病方面的潜在有益作用，尤其关注营养不良性病理。目前，针对诸如活化B细胞核因子κ轻链增强子（NF-κB）和核因子红细胞2相关因子2（NRF2）等信号通路的治疗干预措施在临床和临床前研究中均显示出有限的疗效。因此，需要一种更全面的治疗方法。APE1/Ref-1是一种多功能蛋白，最初被鉴定为参与DNA修复。然而，最新研究揭示了其作为转录因子（包括NF-κB和NRF2）的氧化还原敏感调节剂的额外作用。大量研究报告了APE1/Ref-1在各种疾病中的表达增加，并证明了使用小分子抑制剂APX3330抑制其氧化还原功能的有益效果。尽管这些信号通路在神经肌肉疾病中同样失调，但APE1/Ref-1在骨骼肌中的具体作用仍不清楚，仅有少数研究指出其在该组织中的存在。需要进一步研究来调查APE1/Ref-1在骨骼肌中的作用，并确定其在营养不良性骨骼肌中是上调还是下调，以确定上调或抑制APE1/Ref-1的氧化还原功能是否会减轻慢性炎症和氧化应激增强。42, 641 - 654。
