5-Fluorouracil induces hair loss by inhibiting β-catenin signaling and angiogenesis

Chemotherapy-induced alopecia (CIA) is a side effect of the anticancer drug 5-fluorouracil (5-FU). However, the mechanism of action in hair follicle cells is unclear. This study investigated the mechanism of action of 5-FU on the hair cycle and growth in vitro and in vivo. Intraperitoneal injection of 5-FU into C57BL/6 mice delayed anagen initiation, resulting in small hair follicles. 5-FU inhibited angiogenesis by reducing cluster of differentiation 31⁺ cells, vascular endothelial growth factor, and fetal liver kinase-1 expression in mouse skin tissue and rat vibrissa dermal papilla (rDP) cells. 5-FU induced cell death in rDP cells and keratinocytes by enhancing cell cycle arrest or reducing the ratio of B-cell lymphoma 2 (Bcl-2) to Bcl-2-associated X levels. Immunoblotting and confocal microscopy showed that 5-FU inhibited the nuclear translocation of β-catenin in rDP cells and decreased fibroblast growth factor 7 and 10 secretion. Conversely, molecule-specific inhibitors did not prevent rDP cell death despite protein kinase B and Jun N-terminal kinase activation by 5-FU, indicating their indirect involvement. These results suggest that 5-FU inhibits wingless-related integration site/β-catenin signaling and angiogenesis, resulting in anagen-to-catagen transition and delaying anagen initiation. This study provides foundational data for developing treatments against CIA in patients with cancer undergoing 5-FU chemotherapy.