Multi-omics identifies L-rhamnose as a metabolic regulator that enhances glycolysis to promote hair follicle growth.

BACKGROUND

Hair follicle-regenerating drugs are essential for alopecia treatment, yet their discovery remains a key challenge in dermatology.

PURPOSE: This study aims to identify small molecule compounds that promote hair growth and investigate their underlying mechanisms.

METHODS

A gene panel was designed based on single-cell and bulk RNA-sequencing data, and chemical genomics was employed to screen potential hair-inducing compounds. The lead candidate was validated using an in vivo mouse model of anagen induction and an ex vivo human hair follicle organ culture system. Transcriptomic, metabolomic, and cellular bioenergetics assays were performed to elucidate the potential mechanism, while molecular docking and surface plasmon resonance confirmed its direct protein targets.

RESULTS

Rhamnose was identified as a compound that restored the expression of hair-inducing genes in human dermal papilla cells (hDPCs). Rhamnose accelerated hair follicle regeneration by stimulating the hair cycle progression from telogen to anagen in mice and promoting ex vivo cultured human scalp hair follicle growth. Rhamnose promoted glycolysis in both the mouse model and hDPCs at both transcriptional and metabolic levels. Mechanically, rhamnose exerted its metabolic effects not as a hexose energy substrate, but rather by upregulating hexokinase 2 (HK2)-a key rate-limiting glycolytic enzyme-and directly binding to HK2 to stimulate its activity.

CONCLUSION

This study identifies the natural monosaccharide rhamnose as a metabolic regulator to enhance glycolysis, thereby promoting hair follicle growth, and highlights its potential therapeutic application in alopecia.