Atractylodes macrocephala Koidz. Stimulates Dermal Papilla Cells to Promote Anagen Entry Associated with GSK3β/β-Catenin Signaling

Although Atractylodes macrocephala Koidz. (AM) exhibits various pharmacological properties, its molecular effects and active constituents regarding anagen entry and physiological hair cycle progression remain uncharacterized. This study aimed to investigate the hair growth-promoting efficacy of AM and identify its bioactive compounds and underlying molecular mechanisms. We evaluated AM extract using human dermal papilla cells (DPCs) and a synchronized depilation-induced C57BL/6 mouse model, employing RT-PCR, Western blotting, immunofluorescence, and SwissADME-based pharmacokinetic profiling. AM significantly enhanced DPC proliferation and migration while upregulating paracrine factors (HGF, VEGF, and FGF7). Mechanistically, AM activated Akt, ERK, and p38 MAPKs, leading to GSK3β phosphorylation (Ser9) and subsequent β-catenin stabilization. In vivo, oral AM (60 mg/kg) markedly accelerated the telogen-to-anagen transition, increasing dermal thickness, follicle count, and hair shaft quality without systemic toxicity. Furthermore, cell-based screening and SwissADME prioritized atractylenolide I and III as the chief bioactive sesquiterpenoids driving DPC activation. In conclusion, AM and its key atractylenolides promote anagen entry and hair regrowth, in association with GSK3β phosphorylation and β-catenin stabilization, representing promising natural candidates for promoting physiological hair cycle progression.