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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

Received: 　　Accepted:

Corresponding author: 刘畅　　E-mail:

DOI: 10.13294/j.aps.2025.0059

Citing This Article：

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).