Circadian Clock Regulates Epidermal Endocrine System in Homeostatic Skin Pigmentation

The circadian clock regulates multiple physiological processes in the skin, including local hormone synthesis and pigmentation. However, how circadian regulation interacts with epidermal endocrine signalling in melanocytes remains unclear. In this study, we investigated whether core circadian regulators influence melanogenesis in human melanocytes and explored their potential link to epidermal endocrine factors and pigmentary disease. Primary normal human epidermal melanocytes were analysed following siRNA-mediated knockdown of the core clock genes basic helix-loop-helix ARNT-like protein 1 (BMAL1) and CLOCK circadian regulator (CLOCK). Silencing either gene significantly reduced melanin synthesis and altered the expression of hormone-related factors. Notably, expression of the vitamin D-metabolizing enzyme CYP27A1 was markedly decreased after BMAL1 or CLOCK knockdown, changes that were associated with reduced melanogenic activity. Consistently, immunohistochemical analysis revealed diminished CYP27A1 expression in melanocytes within vitiligo lesions. These findings demonstrate that disruption of circadian clock regulators impairs melanogenesis and is accompanied by alterations in vitamin D-related components. Our results suggest that circadian regulation may modulate pigmentation partly through effects on vitamin D metabolism, providing new insight into the mechanisms underlying pigmentary disorders.