Targeting Circadian Rhythm for the Regulation of Skin Collagen Metabolism

ABSTRACT Background Collagen is essential for maintaining skin structure and function, and the circadian rhythm is known to regulate a wide range of physiological processes. Aims To investigate whether collagen metabolism in human skin fibroblasts exhibits circadian regulation, and to evaluate whether the time‐coordinated application of baicalin at daytime and palmitoyl tripeptide‐1 (PT‐1) at nighttime synergistically promotes collagen fiber formation and improves overall skin quality. Methods A circadian‐synchronized human skin fibroblast model was established. The expression of collagen metabolism‐related genes was analyzed using qPCR and immunofluorescence. Subsequently, an 8‐week topical application study was conducted in mice using a regimen of daytime baicalin and nighttime PT‐1. Finally, a clinical trial involving 30 female participants was conducted, employing the same time‐coordinated application scheme. Results Fibroblasts exhibited opposing day‐night rhythms: genes for collagen assembly (e.g., LOX) peaked during the day, while those involved in synthesis/secretion (e.g., Sec61a2, Mia3, Pde4d, Vps33b) and degradation (e.g., CTSK, MMP1) peaked at night. Time phase‐dependent interventions showed baicalin enhanced daytime assembly, while PT‐1 boosted nighttime synthesis. In mice, a timed day‐night combination therapy increased collagen fiber density. Clinical trial ( n = 30) confirmed the efficacy, showing significant improvements in skin luminance (+16.29%), nasolabial fold depth (−36.35%), and firmness (R2: +24.35%). Conclusions Collagen metabolism is regulated by circadian rhythms. Chronomodulated baicalin and PT‐1 application synergistically optimize collagen metabolism and improve skin quality.