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

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.