Natural compounds regulating skin circadian rhythms: Mechanisms and applications

As a crucial peripheral organ with autonomous circadian rhythm characteristics, the skin's molecular clock is primarily composed of core clock genes such as CLOCK, BMAL1, PER, and CRY. It plays a pivotal role in maintaining skin homeostasis and responding to stress stimuli by regulating processes including cell proliferation and differentiation, DNA damage repair, oxidative stress defense, melanogenesis, and skin immune responses. Accumulating evidence indicates that factors such as ultraviolet (UV) radiation, abnormal light exposure, sleep rhythm disruption, and chronic inflammation can perturb the skin's circadian rhythm, thereby contributing to the development and progression of various skin diseases. In recent years, with the advancement of circadian rhythm research, increasing attention has been focused on the potential role of naturally derived bioactive compounds in regulating skin rhythms. Existing evidence demonstrates that multiple classes of natural compounds can modulate circadian rhythm-related genes and their signaling pathways, exhibiting beneficial effects in disease models such as hyperpigmentation, photoaging, melanoma, and skin barrier damage. However, current studies exhibit significant variations in experimental models, mechanisms of action, and levels of evidence, and there remains considerable controversy regarding whether these compounds exert their effects through direct regulation of the skin's circadian rhythm. This review systematically summarizes the molecular basis of skin circadian rhythm regulation, highlights the research progress of different classes of natural bioactive compounds in regulating rhythm-related skin functions, comprehensively analyzes their key experimental findings, potential signaling pathways, and existing limitations. While these compounds demonstrate considerable translational promise, direct validation of rhythm oscillation parameters in skin models remains insufficient; closing this evidence gap is a prerequisite for clinical application.