Protocatechuic acid modulates the circadian rhythm of keratinocytes and maintains skin barrier integrity.

Background: Circadian rhythms are intrinsic 24-h biological cycles that regulate key physiological processes, including skin cell proliferation, DNA repair, and barrier homeostasis. Disruption of these rhythms accelerates skin aging, compromises barrier integrity, and increases susceptibility to oxidative stress. Protocatechuic acid (PCA) is a naturally occurring compound with antioxidant and anti-inflammatory properties; however, its role in regulating circadian rhythms has not been previously explored. Therefore, this study aimed to investigate the potential of PCA to regulate the circadian rhythm within keratinocytes and the broader effects of PCA on skin physiology.

Methods and results: This potential of PCA as a circadian rhythm modulator in human epidermal keratinocytes was investigated. PCA enhanced circadian activity in a dose-dependent manner, as evidenced by increased amplitude of basic helix-loop-helix ARNT like 1 (BMAL1)-driven bioluminescence. In silico docking revealed strong binding affinity of PCA to retinoic acid-related orphan receptor alpha (RORα), a core clock regulator, suggesting a molecular mechanism of action. PCA also modulated core clock gene expression. Under oxidative stress conditions, PCA reduced reactive oxygen species (ROS) levels and upregulated antioxidant enzymes, including catalase and superoxide dismutase 1. Additionally, PCA promoted skin barrier integrity by increasing structural protein and ceramide-related gene expression and enhanced cellular longevity markers, such as cyclin-dependent kinase inhibitor 1B (CDKN1B) and telomerase reverse transcriptase (TERT).

Conclusions: These findings demonstrate that PCA functions as a multifunctional agent that modulates circadian rhythms, reduces oxidative stress, and supports skin barrier homeostasis and cellular longevity. Overall, PCA shows strong potential as a therapeutic candidate for treating skin disorders associated with circadian disruption and oxidative damage.