Lee Juyeon, Kim Ji-Young, Lee Jun Ho, Lee Kyung-Ha
Department of Molecular Biology, Pusan National University, Busan, 46241, Republic of Korea.
Institute of Systems Biology, Pusan National University, Busan, 46241, Republic of Korea.
Mol Biol Rep. 2025 Jul 28;52(1):765. doi: 10.1007/s11033-025-10880-x.
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.
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).
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.
昼夜节律是内在的24小时生物周期，可调节关键的生理过程，包括皮肤细胞增殖、DNA修复和屏障稳态。这些节律的紊乱会加速皮肤衰老，损害屏障完整性，并增加对氧化应激的易感性。原儿茶酸（PCA）是一种具有抗氧化和抗炎特性的天然化合物；然而，其在调节昼夜节律中的作用此前尚未被探索。因此，本研究旨在探讨PCA调节角质形成细胞内昼夜节律的潜力以及PCA对皮肤生理的更广泛影响。
研究了PCA作为人表皮角质形成细胞中昼夜节律调节剂的这种潜力。PCA以剂量依赖性方式增强昼夜节律活性，碱性螺旋-环-螺旋ARNT样蛋白1（BMAL1）驱动的生物发光幅度增加证明了这一点。计算机对接显示PCA与核心生物钟调节因子视黄酸相关孤儿受体α（RORα）具有很强的结合亲和力，提示了一种作用分子机制。PCA还调节核心生物钟基因表达。在氧化应激条件下，PCA降低了活性氧（ROS）水平并上调了抗氧化酶，包括过氧化氢酶和超氧化物歧化酶1。此外，PCA通过增加结构蛋白和神经酰胺相关基因的表达促进皮肤屏障完整性，并增强了细胞寿命标志物，如细胞周期蛋白依赖性激酶抑制剂1B（CDKN1B）和端粒酶逆转录酶（TERT）。
这些发现表明PCA作为一种多功能剂发挥作用，可调节昼夜节律、降低氧化应激，并支持皮肤屏障稳态和细胞寿命。总体而言，PCA作为治疗与昼夜节律紊乱和氧化损伤相关的皮肤疾病的候选治疗药物具有很强的潜力。
