Natural product rhynchophylline prevents stress-induced hair graying by preserving melanocyte stem cells via the β2 adrenergic pathway suppression.

Norepinephrine (NA), a stress hormone, can accelerate hair graying by binding to β2 adrenergic receptors (βAR) on melanocyte stem cells (McSCs). From this, NA-βAR axis could be a potential target for preventing the stress effect. However, identifying selective blockers for βAR has been a key challenge. Therefore, in this study, advanced computer-aided drug design (CADD) techniques were harnessed to screen natural molecules, leading to the discovery of rhynchophylline as a promising compound. Rhynchophylline exhibited strong and stable binding within the active site of βAR, as verified by molecular docking and dynamic simulation assays. When administered to cells, rhynchophylline effectively inhibited NA-βAR signaling. This intervention resulted in a significant reduction of hair graying in a stress-induced mouse model, from 28.5% to 8.2%. To gain a deeper understanding of the underlying mechanisms, transcriptome sequencing was employed, which revealed that NA might disrupt melanogenesis by affecting intracellular calcium balance and promoting cell apoptosis. Importantly, rhynchophylline acted as a potent inhibitor of these downstream pathways. In conclusion, the study demonstrated that rhynchophylline has the potential to mitigate the negative impact of NA on melanogenesis by targeting βAR, thus offering a promising solution for preventing stress-induced hair graying.