Temporary Cell Cycle Arrest by ALRN-6924: A Novel P53-Targeting Strategy to Protect Human Scalp Hair Follicles Against Cyclophosphamide-Induced Alopecia

The study demonstrates that ALRN-6924, a clinical-stage MDM2/MDMX inhibitor, can protect human hair follicles from damage caused by cyclophosphamide, a chemotherapeutic agent. The drug works by selectively activating p53 to upregulate p21, causing a temporary cell cycle arrest in healthy cells. In the experiment, human anagen scalp hair follicles were pre-treated with ALRN-6924 or a vehicle, followed by 4-HC (a metabolite of cyclophosphamide) or a vehicle. The results showed that ALRN-6924 significantly increased the number of p21+ hair matrix keratinocytes and bulge stem cells, confirming cell cycle arrest. It also reduced melanin clumping, apoptosis, and DNA damage in the hair matrix, and reduced pathological epithelial-mesenchymal transition in hair follicle stem cells. The findings suggest that ALRN-6924 could potentially reduce both acute and permanent hair loss induced by cyclophosphamide.