APE1/Ref-1：多功能生物学、选择性抑制及临床转化之路

摘要(中文译文)

脱嘌呤/脱嘧啶核酸内切酶1/氧化还原因子-1（APE1/Ref-1）是一种多功能应激反应调节因子，协调基因组维护、氧化还原信号传导、RNA生物学和细胞代谢。其表达及亚细胞定位进一步决定疾病状态和严重程度。随着对其生物学复杂性和临床相关性认识的不断深入，APE1/Ref-1日益成为氧化还原应激相关疾病颇具吸引力的治疗靶点。在本综述中，我们旨在整合关于APE1/Ref-1氧化还原功能与修复功能的结构和机制基础的信息，同时关注DNA/RNA形成G-四链体（rG4）生物学、RNA代谢、蛋白质稳态和线粒体功能等领域的新兴证据。我们讨论了调控APE1/Ref-1表达、活性及转运的机制，这些机制在生理和疾病背景下动态影响其功能。我们特别强调治疗策略，包括氧化还原特异性抑制、靶向内切酶的方法以及基因扰动，这些策略在不同疾病模型中产生不同的效应。对APE1/Ref-1生物学不断深入的理解加速了治疗开发，尤其是通过氧化还原选择性靶向策略。小分子抑制剂如APX3330以及新一代类似物APX2009和APX2014已推进至涵盖癌症、炎症性疾病和眼部疾病的治疗应用。对APE1/Ref-1情境依赖性和多功能作用的持续研究，连同机制导向治疗设计的进展，正在稳步增强APE1/Ref-1靶向治疗的转化潜力。

Abstract

Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional stress-response regulator that coordinates genome maintenance, redox signaling, RNA biology, and cellular metabolism. Its expression and subcellular localization further determine disease states and severity. The growing appreciation of its biological complexity and clinical relevance makes APE1/Ref-1 an increasingly attractive therapeutic target for redox-stress-related diseases. In this review, we aim to consolidate information on the structural and mechanistic basis of APE1/Ref-1 redox and repair functions, while recognizing emerging evidence in DNA/RNA-forming G-quadruplex (rG4) biology, RNA metabolism, protein homeostasis, and mitochondrial function. We discuss mechanisms regulating APE1/Ref-1 expression, activity, and trafficking, which dynamically influence function in physiological and disease contexts. We specifically emphasize therapeutic strategies including redox-specific inhibition, endonuclease-targeted approaches, and genetic perturbations that result in distinct effects across disease models. Evolving understanding of APE1/Ref-1 biology has accelerated therapeutic development, particularly through redox-selective targeting strategies. Small-molecule inhibitors such as APX3330 and new-generation analogs like APX2009 and APX2014 have advanced into therapeutic applications spanning cancer, inflammatory disorders, and ocular diseases. Continued investigation into the context-dependent and multifunctional roles of APE1/Ref-1, together with the progression of mechanism-informed therapeutic design, is steadily strengthening the translational potential of APE1/Ref-1-directed therapies.

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