当期文章

生物钟靶向小分子化合物干预代谢性疾病的研究进展

王清晴, 刘畅^*

中国药科大学生命科学与技术学院，南京 211198

摘要

昼夜节律由内源性生物钟通过核心时钟基因的转录-翻译反馈回路(transcription-translation feedback loop, TTFL)调控，维持生物体的24 h 的行为和生理周期。在哺乳动物中，视交叉上核(suprachiasmatic nucleus, SCN)作为中枢节律起搏器，通过调控时钟基因(如CLOCK、BMAL1、PER、CRY等)的表达，同步协调全身生理活动的周期性。外周组织与细胞的分子钟通过TTFL与SCN同步，共同维持代谢、免疫及能量稳态的昼夜节律。研究表明，昼夜节律紊乱可通过引发糖脂代谢失衡、胰岛素信号异常及慢性炎症反应等机制，显著增加肥胖、2 型糖尿病、代谢综合征等疾病的发生风险。近年来，靶向核心时钟组分(如CRY、REV-ERB、ROR等)的小分子化合物通过稳定或抑制TTFL关键蛋白活性，在代谢性疾病干预中显示出独特优势。本文系统综述了此类生物钟靶向小分子化合物的作用机制及研究进展，并对其临床转化面临的挑战与未来发展方向进行探讨，以期为代谢性疾病的时序治疗提供新思路。

关键词： 昼夜节律; 小分子化合物; 代谢性疾病; 生理稳态

Research progress on biological clock-targeting small-molecule compounds for intervention in metabolic diseases

WANG Qing-Qing, LIU Chang^*

School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China

Abstract

The circadian rhythm regulates the 24-hour physiological and behavioral cycles through endogenous molecular clocks governed by core clock genes via the transcription-translation feedback loop (TTFL). In mammals, the suprachiasmatic nucleus (SCN) serves as the central pacemaker, coordinating the timing of physiological processes throughout the body by regulating clock genes such as CLOCK, BMAL1, PER, and CRY. The molecular clocks of peripheral tissues and cells are synchronized by the SCN through TTFLs to regulate metabolism, immunity, and energy homeostasis. Numerous studies indicate that circadian rhythm disruption is closely related to obesity, type 2 diabetes, metabolic syndrome and other diseases, and the mechanism involves the dysregulation of glucose and lipid metabolism, abnormal insulin signaling and low-grade inflammation. In recent years, small-molecule compounds targeting the core clock components such as CRY, REV-ERB, and ROR have been identified and shown potential to modulate metabolic diseases by stabilizing or inhibiting the activity of key clock proteins. This review summarizes the mechanisms and advances in these compounds, and explores the challenges and future directions for their clinical translation, providing insights for chronotherapybased metabolic disease interventions.

Key words: Circadian rhythm; small-molecule compounds; metabolic diseases; physiological homeostasis

收稿日期：　　录用日期：

通讯作者：刘畅　　E-mail:

DOI: 10.13294/j.aps.2025.0059

引用本文：

王清晴, 刘畅. 生物钟靶向小分子化合物干预代谢性疾病的研究进展[J]. 生理学报 2025; 77 (4): 641-652.

WANG Qing-Qing, LIU Chang. Research progress on biological clock-targeting small-molecule compounds for intervention in metabolic diseases. Acta Physiol Sin 2025; 77 (4): 641-652 (in Chinese with English abstract).