【摘要】 昼夜节律时钟作为生物体中高度保守的时间维持系统，可通过精确调控基因表达的周期性波动维持机体生理稳态。大量临床与实验证据表明，昼夜节律紊乱与多种恶性肿瘤的发生发展密切相关。研究显示，肿瘤组织中存在昼夜节律基因表达谱的特征性改变，主要表现为核心时钟元件（特别是CLOCK与BMAL1）的功能失调及其下游靶基因的广泛调控异常。值得注意的是，CLOCK基因展现出非经典致癌功能，包括通过组蛋白乙酰转移酶活性进行表观遗传调控，以及对癌症通路实施不依赖于昼夜节律的调控作用。本文系统阐述了CLOCK/BMAL1介导的致癌机制，涵盖细胞周期调控、DNA损伤应答、代谢重编程及肿瘤微环境重塑等多维度效应。在治疗策略方面，本文重点关注时序营养干预、节律药理学调控及治疗方案优化等前沿方向，并对未来发展前景进行展望。本文聚焦的研究突破不仅加深了我们对昼夜节律调控在癌症生物学中重要作用的理解，更为时序治疗肿瘤学的发展提供了新视角，尤其是通过靶向昼夜节律蛋白的非经典功能来开发创新的抗癌策略。更多还原

【Abstract】 The circadian clock is a highly conserved timekeeping system in organisms, which maintains physiological homeostasis by precisely regulating periodic fluctuations in gene expression. Substantial clinical and experimental evidence has established a close association between circadian rhythm disruption and the development of various malignancies. Research has revealed characteristic alterations in the circadian gene expression profiles in tumor tissues, primarily manifested as a dysfunction of core clock components(particularly circadian locomotor output cycles kaput(CLOCK) and brain and muscle ARNT-like 1(BMAL1)) and the widespread dysregulation of their downstream target genes. Notably, CLOCK demonstrates non-canonical oncogenic functions, including epigenetic regulation via histone acetyltransferase activity and the circadian-independent modulation of cancer pathways. This review systematically elaborates on the oncogenic mechanisms mediated by CLOCK/BMAL1, encompassing multidimensional effects such as cell cycle control, DNA damage response, metabolic reprogramming, and tumor microenvironment(TME) remodeling. Regarding the therapeutic strategies, we focus on cutting-edge approaches such as chrononutritional interventions, chronopharmacological modulation, and treatment regimen optimization, along with a discussion of future perspectives. The research breakthroughs highlighted in this work not only deepen our understanding of the crucial role of circadian regulation in cancer biology but also provide novel insights for the development of chronotherapeutic oncology, particularly through targeting the non-canonical functions of circadian proteins to develop innovative anti-cancer strategies.更多还原