Creatine Supplementation Enhances Fat Graft Survival by Mitochondrial Protection and Revascularization Promotion

ABSTRACT Autologous fat grafting is compromised by post‐grafting ischemic necrosis and volumetric resorption, clinical challenges stemming from inadequate vascularization and metabolic stress. Here, we identify oral creatine supplementation as a translatable metabolic therapy to enhance fat graft survival. Through adipose organoids and a murine grafting model, we demonstrate that creatine stabilizes mitochondrial membrane potential (ΔΨm), reduces reactive oxygen species (ROS), and redirects energy production toward non‐mitochondrial ATP synthesis, collectively promoting adipocyte survival and revascularization. Mechanistically, creatine activates a phosphocreatine‐kinase shuttle to sustain ATP pools independently of oxidative phosphorylation, while concurrently mitigating electron transport chain‐derived oxidative damage. The therapeutic equivalence of systemic and localized delivery routes, combined with creatine's FDA‐approved safety profile, positions this intervention as a clinically viable strategy to improve fat grafting outcomes.