GHK‐Cu Delays Aging Through the Repair of Mitochondrial Dysfunction

ABSTRACT

Althugh glycyl‐L‐histidyl‐L‐lysine copper (GHK‐Cu) shows antiaging potential, its precise molecular mechanisms remain unclear. Using Caenorhabditis elegans ( C. elegans ) as an in vivo aging model, we observed that GHK‐Cu extended organismal lifespan and improved stress resilience. Network pharmacology uncovers over 70% overlap between its antiaging pathways and cascades repairing mitochondrial dysfunction. Molecular docking and dynamics simulations verify stable binding of GHK‐Cu to mitogen‐activated protein kinase 1 (MAPK1), nuclear factor kappa B subunit 1 (NFKB1), and caspase 3 (CASP3), whereas RT‐PCR and Western blot assays confirm the regulatory effects of GHK‐Cu on the transcriptional and translational expression of these targets. Cellular assays in an H ₂ O ₂ ‐induced senescence model show that GHK‐Cu pretreatment mitigates oxidative damage and cellular senescence in a dose‐dependent manner. Moreover, GHK‐Cu restores mitochondrial homeostasis by stabilizing membrane potential, boosting oxygen consumption and adenosine triphosphate (ATP) production, and inhibiting pathological mitochondrial permeability transition pore (mPTP) opening. In conclusion, GHK‐Cu exerts antiaging effects by attenuating oxidative stress and preserving mitochondrial homeostasis via modulation of MAPK1, NFKB1, and CASP3. These results support the translational prospects of GHK‐Cu as a mitochondrial‐targeted protectant for dermatological and functional healthcare use.